3qlh - Revision history

OCA at 14:06, 13 March 2024

OCA — Wed, 13 Mar 2024 14:06:02 GMT

←Older revision		Revision as of 14:06, 13 March 2024
Line 3:		Line 3:
	<StructureSection load='3qlh' size='340' side='right'caption='[[3qlh]], [[Resolution\|resolution]] 2.70Å' scene=''>		<StructureSection load='3qlh' size='340' side='right'caption='[[3qlh]], [[Resolution\|resolution]] 2.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3qlh]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Dulacia_guianensis Dulacia guianensis] and [https://en.wikipedia.org/wiki/Hiv-1 Hiv-~~1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QLH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QLH FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3qlh]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_type_1_BH10 Human immunodeficiency virus type 1 BH10]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QLH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QLH FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=MNK:(2S)-5,7-DIHYDROXY-9-METHYL-2-(PROP-1-EN-2-YL)-1,2,3,4-TETRAHYDRO-6H-BENZO[7]ANNULEN-6-ONE'>MNK</scene>, <scene name='pdbligand=T27:4-{[4-({4-[(E)-2-CYANOETHENYL]-2,6-DIMETHYLPHENYL}AMINO)PYRIMIDIN-2-YL]AMINO}BENZONITRILE'>T27</scene>~~</td></tr>~~	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.7Å</td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">gag-pol, POL ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11678 HIV-1])~~</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=MNK:(2S)-5,7-DIHYDROXY-9-METHYL-2-(PROP-1-EN-2-YL)-1,2,3,4-TETRAHYDRO-6H-BENZO[7]ANNULEN-6-ONE'>MNK</scene>, <scene name='pdbligand=T27:4-{[4-({4-[(E)-2-CYANOETHENYL]-2,6-DIMETHYLPHENYL}AMINO)PYRIMIDIN-2-YL]AMINO}BENZONITRILE'>T27</scene></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3qlh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qlh OCA], [https://pdbe.org/3qlh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qlh RCSB], [https://www.ebi.ac.uk/pdbsum/3qlh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qlh ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3qlh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qlh OCA], [https://pdbe.org/3qlh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qlh RCSB], [https://www.ebi.ac.uk/pdbsum/3qlh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qlh ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/POL_HV1B1 POL_HV1B1]] Gag-Pol polyprotein and Gag polyprotein may regulate their own translation, by the binding genomic RNA in the 5'-UTR. At low concentration, Gag-Pol and Gag would promote translation, whereas at high concentration, the polyproteins encapsidate genomic RNA and then shutt off translation (By similarity).<ref>PMID:9658129</ref> Matrix protein p17 has two main functions: in infected cell, it targets Gag and Gag-pol polyproteins to the plasma membrane via a multipartite membrane-binding signal, that includes its myristoylated N-terminus. The second function is to play a role in nuclear localization of the viral genome at the very start of cell infection. Matrix protein is the part of the pre-integration complex. It binds in the cytoplasm the human BAF protein which prevent autointegration of the viral genome, and might be included in virions at the ration of zero to 3 BAF dimer per virion. The myristoylation signal and the NLS thus exert conflicting influences its subcellular localization. The key regulation of these motifs might be phosphorylation of a portion of MA molecules on the C-terminal tyrosine at the time of virus maturation, by virion-associated cellular tyrosine kinase. Implicated in the release from host cell mediated by Vpu (By similarity).<ref>PMID:9658129</ref> Capsid protein p24 forms the conical core that encapsulates the genomic RNA-nucleocapsid complex in the virion. Most core are conical, with only 7% tubular. The core is constituted by capsid protein hexamer subunits. The core is disassembled soon after virion entry. Interaction with human PPIA/CYPA protects the virus from restriction by human TRIM5-alpha and from an unknown antiviral activity in human cells. This capsid restriction by TRIM5 is one of the factors which restricts HIV-1 to the human species (By similarity).<ref>PMID:9658129</ref> Nucleocapsid protein p7 encapsulates and protects viral dimeric unspliced (genomic) RNA. Binds these RNAs through its zinc fingers. Facilitates rearangement of nucleic acid secondary structure during retrotranscription of genomic RNA. This capability is referred to as nucleic acid chaperone activity (By similarity).<ref>PMID:9658129</ref> The aspartyl protease mediates proteolytic cleavages of Gag and Gag-Pol polyproteins during or shortly after the release of the virion from the plasma membrane. Cleavages take place as an ordered, step-wise cascade to yield mature proteins. This process is called maturation. Displays maximal activity during the budding process just prior to particle release from the cell. Also cleaves Nef and Vif, probably concomitantly with viral structural proteins on maturation of virus particles (By similarity).<ref>PMID:9658129</ref> Reverse transcriptase/ribonuclease H (RT) is a multifunctional enzyme that converts the viral RNA genome into dsDNA in the cytoplasm, shortly after virus entry into the cell. This enzyme displays a DNA polymerase activity that can copy either DNA or RNA templates, and a ribonuclease H (RNase H) activity that cleaves the RNA strand of RNA-DNA heteroduplexes in a partially processive 3' to 5' endonucleasic mode. Conversion of viral genomic RNA into dsDNA requires many steps. A tRNA(3)-Lys binds to the primer-binding site (PBS) situated at the 5'-end of the viral RNA. RT uses the 3' end of the tRNA primer to perform a short round of RNA-dependent minus-strand DNA synthesis. The reading proceeds through the U5 region and ends after the repeated (R) region which is present at both ends of viral RNA. The portion of the RNA-DNA heteroduplex is digested by the RNase H, resulting in a ssDNA product attached to the tRNA primer. This ssDNA/tRNA hybridizes with the identical R region situated at the 3' end of viral RNA. This template exchange, known as minus-strand DNA strong stop transfer, can be either intra- or intermolecular. RT uses the 3' end of this newly synthesized short ssDNA to perform the RNA-dependent minus-strand DNA synthesis of the whole template. RNase H digests the RNA template except for two polypurine tracts (PPTs) situated at the 5'-end and near the center of the genome. It is not clear if both polymerase and RNase H activities are simultaneous. RNase H probably can proceed both in a polymerase-dependent (RNA cut into small fragments by the same RT performing DNA synthesis) and a polymerase-independent mode (cleavage of remaining RNA fragments by free RTs). Secondly, RT performs DNA-directed plus-strand DNA synthesis using the PPTs that have not been removed by RNase H as primers. PPTs and tRNA primers are then removed by RNase H. The 3' and 5' ssDNA PBS regions hybridize to form a circular dsDNA intermediate. Strand displacement synthesis by RT to the PBS and PPT ends produces a blunt ended, linear dsDNA copy of the viral genome that includes long terminal repeats (LTRs) at both ends (By similarity).<ref>PMID:9658129</ref> Integrase catalyzes viral DNA integration into the host chromosome, by performing a series of DNA cutting and joining reactions. This enzyme activity takes place after virion entry into a cell and reverse transcription of the RNA genome in dsDNA. The first step in the integration process is 3' processing. This step requires a complex comprising the viral genome, matrix protein, Vpr and integrase. This complex is called the pre-integration complex (PIC). The integrase protein removes 2 nucleotides from each 3' end of the viral DNA, leaving recessed CA OH's at the 3' ends. In the second step, the PIC enters cell nucleus. This process is mediated through integrase and Vpr proteins, and allows the virus to infect a non dividing cell. This ability to enter the nucleus is specific of lentiviruses, other retroviruses cannot and rely on cell division to access cell chromosomes. In the third step, termed strand transfer, the integrase protein joins the previously processed 3' ends to the 5' ends of strands of target cellular DNA at the site of integration. The 5'-ends are produced by integrase-catalyzed staggered cuts, 5 bp apart. A Y-shaped, gapped, recombination intermediate results, with the 5'-ends of the viral DNA strands and the 3' ends of target DNA strands remaining unjoined, flanking a gap of 5 bp. The last step is viral DNA integration into host chromosome. This involves host DNA repair synthesis in which the 5 bp gaps between the unjoined strands are filled in and then ligated. Since this process occurs at both cuts flanking the HIV genome, a 5 bp duplication of host DNA is produced at the ends of HIV-1 integration. Alternatively, Integrase may catalyze the excision of viral DNA just after strand transfer, this is termed disintegration (By similarity).<ref>PMID:9658129</ref>	+	[https://www.uniprot.org/uniprot/POL_HV1B1 POL_HV1B1] Gag-Pol polyprotein and Gag polyprotein may regulate their own translation, by the binding genomic RNA in the 5'-UTR. At low concentration, Gag-Pol and Gag would promote translation, whereas at high concentration, the polyproteins encapsidate genomic RNA and then shutt off translation (By similarity).<ref>PMID:9658129</ref> Matrix protein p17 has two main functions: in infected cell, it targets Gag and Gag-pol polyproteins to the plasma membrane via a multipartite membrane-binding signal, that includes its myristoylated N-terminus. The second function is to play a role in nuclear localization of the viral genome at the very start of cell infection. Matrix protein is the part of the pre-integration complex. It binds in the cytoplasm the human BAF protein which prevent autointegration of the viral genome, and might be included in virions at the ration of zero to 3 BAF dimer per virion. The myristoylation signal and the NLS thus exert conflicting influences its subcellular localization. The key regulation of these motifs might be phosphorylation of a portion of MA molecules on the C-terminal tyrosine at the time of virus maturation, by virion-associated cellular tyrosine kinase. Implicated in the release from host cell mediated by Vpu (By similarity).<ref>PMID:9658129</ref> Capsid protein p24 forms the conical core that encapsulates the genomic RNA-nucleocapsid complex in the virion. Most core are conical, with only 7% tubular. The core is constituted by capsid protein hexamer subunits. The core is disassembled soon after virion entry. Interaction with human PPIA/CYPA protects the virus from restriction by human TRIM5-alpha and from an unknown antiviral activity in human cells. This capsid restriction by TRIM5 is one of the factors which restricts HIV-1 to the human species (By similarity).<ref>PMID:9658129</ref> Nucleocapsid protein p7 encapsulates and protects viral dimeric unspliced (genomic) RNA. Binds these RNAs through its zinc fingers. Facilitates rearangement of nucleic acid secondary structure during retrotranscription of genomic RNA. This capability is referred to as nucleic acid chaperone activity (By similarity).<ref>PMID:9658129</ref> The aspartyl protease mediates proteolytic cleavages of Gag and Gag-Pol polyproteins during or shortly after the release of the virion from the plasma membrane. Cleavages take place as an ordered, step-wise cascade to yield mature proteins. This process is called maturation. Displays maximal activity during the budding process just prior to particle release from the cell. Also cleaves Nef and Vif, probably concomitantly with viral structural proteins on maturation of virus particles (By similarity).<ref>PMID:9658129</ref> Reverse transcriptase/ribonuclease H (RT) is a multifunctional enzyme that converts the viral RNA genome into dsDNA in the cytoplasm, shortly after virus entry into the cell. This enzyme displays a DNA polymerase activity that can copy either DNA or RNA templates, and a ribonuclease H (RNase H) activity that cleaves the RNA strand of RNA-DNA heteroduplexes in a partially processive 3' to 5' endonucleasic mode. Conversion of viral genomic RNA into dsDNA requires many steps. A tRNA(3)-Lys binds to the primer-binding site (PBS) situated at the 5'-end of the viral RNA. RT uses the 3' end of the tRNA primer to perform a short round of RNA-dependent minus-strand DNA synthesis. The reading proceeds through the U5 region and ends after the repeated (R) region which is present at both ends of viral RNA. The portion of the RNA-DNA heteroduplex is digested by the RNase H, resulting in a ssDNA product attached to the tRNA primer. This ssDNA/tRNA hybridizes with the identical R region situated at the 3' end of viral RNA. This template exchange, known as minus-strand DNA strong stop transfer, can be either intra- or intermolecular. RT uses the 3' end of this newly synthesized short ssDNA to perform the RNA-dependent minus-strand DNA synthesis of the whole template. RNase H digests the RNA template except for two polypurine tracts (PPTs) situated at the 5'-end and near the center of the genome. It is not clear if both polymerase and RNase H activities are simultaneous. RNase H probably can proceed both in a polymerase-dependent (RNA cut into small fragments by the same RT performing DNA synthesis) and a polymerase-independent mode (cleavage of remaining RNA fragments by free RTs). Secondly, RT performs DNA-directed plus-strand DNA synthesis using the PPTs that have not been removed by RNase H as primers. PPTs and tRNA primers are then removed by RNase H. The 3' and 5' ssDNA PBS regions hybridize to form a circular dsDNA intermediate. Strand displacement synthesis by RT to the PBS and PPT ends produces a blunt ended, linear dsDNA copy of the viral genome that includes long terminal repeats (LTRs) at both ends (By similarity).<ref>PMID:9658129</ref> Integrase catalyzes viral DNA integration into the host chromosome, by performing a series of DNA cutting and joining reactions. This enzyme activity takes place after virion entry into a cell and reverse transcription of the RNA genome in dsDNA. The first step in the integration process is 3' processing. This step requires a complex comprising the viral genome, matrix protein, Vpr and integrase. This complex is called the pre-integration complex (PIC). The integrase protein removes 2 nucleotides from each 3' end of the viral DNA, leaving recessed CA OH's at the 3' ends. In the second step, the PIC enters cell nucleus. This process is mediated through integrase and Vpr proteins, and allows the virus to infect a non dividing cell. This ability to enter the nucleus is specific of lentiviruses, other retroviruses cannot and rely on cell division to access cell chromosomes. In the third step, termed strand transfer, the integrase protein joins the previously processed 3' ends to the 5' ends of strands of target cellular DNA at the site of integration. The 5'-ends are produced by integrase-catalyzed staggered cuts, 5 bp apart. A Y-shaped, gapped, recombination intermediate results, with the 5'-ends of the viral DNA strands and the 3' ends of target DNA strands remaining unjoined, flanking a gap of 5 bp. The last step is viral DNA integration into host chromosome. This involves host DNA repair synthesis in which the 5 bp gaps between the unjoined strands are filled in and then ligated. Since this process occurs at both cuts flanking the HIV genome, a 5 bp duplication of host DNA is produced at the ends of HIV-1 integration. Alternatively, Integrase may catalyze the excision of viral DNA just after strand transfer, this is termed disintegration (By similarity).<ref>PMID:9658129</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	The alpha-hydroxytroplone, manicol (5,7-dihydroxy-2-isopropenyl-9-methyl-1,2,3,4-tetrahydro-benzocyclohepten- 6-one), potently and specifically inhibits ribonuclease H (RNase H) activity of human immunodeficiency virus reverse transcriptase (HIV RT) in vitro. However, manicol was ineffective in reducing virus replication in culture. Ongoing efforts to improve the potency and specificity over the lead compound led us to synthesize 14 manicol derivatives that retain the divalent metal-chelating alpha-hydroxytropolone pharmacophore. These efforts were augmented by a high resolution structure of p66/p51 HIV-1 RT containing the nonnucleoside reverse transcriptase inhibitor (NNRTI), TMC278 and manicol in the DNA polymerase and RNase H active sites, respectively. We demonstrate here that several modified alpha-hydroxytropolones exhibit antiviral activity at noncytotoxic concentrations. Inclusion of RNase H active site mutants indicated that manicol analogues can occupy an additional site in or around the DNA polymerase catalytic center. Collectively, our studies will promote future structure-based design of improved alpha-hydroxytropolones to complement the NRTI and NNRTI currently in clinical use.	+
-		+
-	Synthesis, activity, and structural analysis of novel alpha-hydroxytropolone inhibitors of human immunodeficiency virus reverse transcriptase-associated ribonuclease H.,Chung S, Himmel DM, Jiang JK, Wojtak K, Bauman JD, Rausch JW, Wilson JA, Beutler JA, Thomas CJ, Arnold E, Le Grice SF J Med Chem. 2011 Jul 14;54(13):4462-73. Epub 2011 Jun 2. PMID:21568335<ref>PMID:21568335</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 3qlh" style="background-color:#fffaf0;"></div~~>	+

	==See Also==		==See Also==
Line 26:		Line 17:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Dulacia guianensis]]~~	+	[[Category: Human immunodeficiency virus type 1 BH10]]
-	~~[[Category: Hiv-~~1]]	+
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Arnold, E]]	+	[[Category: Arnold E]]
-	[[Category: Bauman~~, J D~~]]	+	[[Category: Bauman JD]]
-	[[Category: Himmel~~, D M~~]]	+	[[Category: Himmel DM]]
-	[[Category: Wojtak, K]]	+	[[Category: Wojtak K]]
-	~~[[Category: Divalent cation chelator]]~~	+
-	~~[[Category: Hydrolase-inhibitor complex]]~~	+
-	~~[[Category: Non-nucleoside rt inhibitor]]~~	+
-	~~[[Category: Rnase h inhibitor]]~~	+
-	~~[[Category: Structure-based drug design]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Tropolone derivative~~]]	+

OCA at 06:13, 8 June 2022

OCA — Wed, 08 Jun 2022 06:13:44 GMT

←Older revision		Revision as of 06:13, 8 June 2022
Line 1:		Line 1:

	==HIV-1 Reverse Transcriptase in Complex with Manicol at the RNase H Active Site and TMC278 (Rilpivirine) at the NNRTI Binding Pocket==		==HIV-1 Reverse Transcriptase in Complex with Manicol at the RNase H Active Site and TMC278 (Rilpivirine) at the NNRTI Binding Pocket==
-	<StructureSection load='3qlh' size='340' side='right' caption='[[3qlh]], [[Resolution\|resolution]] 2.70Å' scene=''>	+	<StructureSection load='3qlh' size='340' side='right'caption='[[3qlh]], [[Resolution\|resolution]] 2.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3qlh]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/Dulacia_guianensis Dulacia guianensis] and [~~http~~://en.wikipedia.org/wiki/Hiv-1 Hiv-1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QLH OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3QLH FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3qlh]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Dulacia_guianensis Dulacia guianensis] and [https://en.wikipedia.org/wiki/Hiv-1 Hiv-1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QLH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QLH FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=MNK:(2S)-5,7-DIHYDROXY-9-METHYL-2-(PROP-1-EN-2-YL)-1,2,3,4-TETRAHYDRO-6H-BENZO[7]ANNULEN-6-ONE'>MNK</scene>, <scene name='pdbligand=T27:4-{[4-({4-[(E)-2-CYANOETHENYL]-2,6-DIMETHYLPHENYL}AMINO)PYRIMIDIN-2-YL]AMINO}BENZONITRILE'>T27</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=MNK:(2S)-5,7-DIHYDROXY-9-METHYL-2-(PROP-1-EN-2-YL)-1,2,3,4-TETRAHYDRO-6H-BENZO[7]ANNULEN-6-ONE'>MNK</scene>, <scene name='pdbligand=T27:4-{[4-({4-[(E)-2-CYANOETHENYL]-2,6-DIMETHYLPHENYL}AMINO)PYRIMIDIN-2-YL]AMINO}BENZONITRILE'>T27</scene></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">gag-pol, POL ([~~http~~://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11678 HIV-1])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">gag-pol, POL ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11678 HIV-1])</td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3qlh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qlh OCA], [~~http~~://pdbe.org/3qlh PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3qlh RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3qlh PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3qlh ProSAT]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3qlh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qlh OCA], [https://pdbe.org/3qlh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qlh RCSB], [https://www.ebi.ac.uk/pdbsum/3qlh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qlh ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/POL_HV1B1 POL_HV1B1]] Gag-Pol polyprotein and Gag polyprotein may regulate their own translation, by the binding genomic RNA in the 5'-UTR. At low concentration, Gag-Pol and Gag would promote translation, whereas at high concentration, the polyproteins encapsidate genomic RNA and then shutt off translation (By similarity).<ref>PMID:9658129</ref> Matrix protein p17 has two main functions: in infected cell, it targets Gag and Gag-pol polyproteins to the plasma membrane via a multipartite membrane-binding signal, that includes its myristoylated N-terminus. The second function is to play a role in nuclear localization of the viral genome at the very start of cell infection. Matrix protein is the part of the pre-integration complex. It binds in the cytoplasm the human BAF protein which prevent autointegration of the viral genome, and might be included in virions at the ration of zero to 3 BAF dimer per virion. The myristoylation signal and the NLS thus exert conflicting influences its subcellular localization. The key regulation of these motifs might be phosphorylation of a portion of MA molecules on the C-terminal tyrosine at the time of virus maturation, by virion-associated cellular tyrosine kinase. Implicated in the release from host cell mediated by Vpu (By similarity).<ref>PMID:9658129</ref> Capsid protein p24 forms the conical core that encapsulates the genomic RNA-nucleocapsid complex in the virion. Most core are conical, with only 7% tubular. The core is constituted by capsid protein hexamer subunits. The core is disassembled soon after virion entry. Interaction with human PPIA/CYPA protects the virus from restriction by human TRIM5-alpha and from an unknown antiviral activity in human cells. This capsid restriction by TRIM5 is one of the factors which restricts HIV-1 to the human species (By similarity).<ref>PMID:9658129</ref> Nucleocapsid protein p7 encapsulates and protects viral dimeric unspliced (genomic) RNA. Binds these RNAs through its zinc fingers. Facilitates rearangement of nucleic acid secondary structure during retrotranscription of genomic RNA. This capability is referred to as nucleic acid chaperone activity (By similarity).<ref>PMID:9658129</ref> The aspartyl protease mediates proteolytic cleavages of Gag and Gag-Pol polyproteins during or shortly after the release of the virion from the plasma membrane. Cleavages take place as an ordered, step-wise cascade to yield mature proteins. This process is called maturation. Displays maximal activity during the budding process just prior to particle release from the cell. Also cleaves Nef and Vif, probably concomitantly with viral structural proteins on maturation of virus particles (By similarity).<ref>PMID:9658129</ref> Reverse transcriptase/ribonuclease H (RT) is a multifunctional enzyme that converts the viral RNA genome into dsDNA in the cytoplasm, shortly after virus entry into the cell. This enzyme displays a DNA polymerase activity that can copy either DNA or RNA templates, and a ribonuclease H (RNase H) activity that cleaves the RNA strand of RNA-DNA heteroduplexes in a partially processive 3' to 5' endonucleasic mode. Conversion of viral genomic RNA into dsDNA requires many steps. A tRNA(3)-Lys binds to the primer-binding site (PBS) situated at the 5'-end of the viral RNA. RT uses the 3' end of the tRNA primer to perform a short round of RNA-dependent minus-strand DNA synthesis. The reading proceeds through the U5 region and ends after the repeated (R) region which is present at both ends of viral RNA. The portion of the RNA-DNA heteroduplex is digested by the RNase H, resulting in a ssDNA product attached to the tRNA primer. This ssDNA/tRNA hybridizes with the identical R region situated at the 3' end of viral RNA. This template exchange, known as minus-strand DNA strong stop transfer, can be either intra- or intermolecular. RT uses the 3' end of this newly synthesized short ssDNA to perform the RNA-dependent minus-strand DNA synthesis of the whole template. RNase H digests the RNA template except for two polypurine tracts (PPTs) situated at the 5'-end and near the center of the genome. It is not clear if both polymerase and RNase H activities are simultaneous. RNase H probably can proceed both in a polymerase-dependent (RNA cut into small fragments by the same RT performing DNA synthesis) and a polymerase-independent mode (cleavage of remaining RNA fragments by free RTs). Secondly, RT performs DNA-directed plus-strand DNA synthesis using the PPTs that have not been removed by RNase H as primers. PPTs and tRNA primers are then removed by RNase H. The 3' and 5' ssDNA PBS regions hybridize to form a circular dsDNA intermediate. Strand displacement synthesis by RT to the PBS and PPT ends produces a blunt ended, linear dsDNA copy of the viral genome that includes long terminal repeats (LTRs) at both ends (By similarity).<ref>PMID:9658129</ref> Integrase catalyzes viral DNA integration into the host chromosome, by performing a series of DNA cutting and joining reactions. This enzyme activity takes place after virion entry into a cell and reverse transcription of the RNA genome in dsDNA. The first step in the integration process is 3' processing. This step requires a complex comprising the viral genome, matrix protein, Vpr and integrase. This complex is called the pre-integration complex (PIC). The integrase protein removes 2 nucleotides from each 3' end of the viral DNA, leaving recessed CA OH's at the 3' ends. In the second step, the PIC enters cell nucleus. This process is mediated through integrase and Vpr proteins, and allows the virus to infect a non dividing cell. This ability to enter the nucleus is specific of lentiviruses, other retroviruses cannot and rely on cell division to access cell chromosomes. In the third step, termed strand transfer, the integrase protein joins the previously processed 3' ends to the 5' ends of strands of target cellular DNA at the site of integration. The 5'-ends are produced by integrase-catalyzed staggered cuts, 5 bp apart. A Y-shaped, gapped, recombination intermediate results, with the 5'-ends of the viral DNA strands and the 3' ends of target DNA strands remaining unjoined, flanking a gap of 5 bp. The last step is viral DNA integration into host chromosome. This involves host DNA repair synthesis in which the 5 bp gaps between the unjoined strands are filled in and then ligated. Since this process occurs at both cuts flanking the HIV genome, a 5 bp duplication of host DNA is produced at the ends of HIV-1 integration. Alternatively, Integrase may catalyze the excision of viral DNA just after strand transfer, this is termed disintegration (By similarity).<ref>PMID:9658129</ref>	+	[[https://www.uniprot.org/uniprot/POL_HV1B1 POL_HV1B1]] Gag-Pol polyprotein and Gag polyprotein may regulate their own translation, by the binding genomic RNA in the 5'-UTR. At low concentration, Gag-Pol and Gag would promote translation, whereas at high concentration, the polyproteins encapsidate genomic RNA and then shutt off translation (By similarity).<ref>PMID:9658129</ref> Matrix protein p17 has two main functions: in infected cell, it targets Gag and Gag-pol polyproteins to the plasma membrane via a multipartite membrane-binding signal, that includes its myristoylated N-terminus. The second function is to play a role in nuclear localization of the viral genome at the very start of cell infection. Matrix protein is the part of the pre-integration complex. It binds in the cytoplasm the human BAF protein which prevent autointegration of the viral genome, and might be included in virions at the ration of zero to 3 BAF dimer per virion. The myristoylation signal and the NLS thus exert conflicting influences its subcellular localization. The key regulation of these motifs might be phosphorylation of a portion of MA molecules on the C-terminal tyrosine at the time of virus maturation, by virion-associated cellular tyrosine kinase. Implicated in the release from host cell mediated by Vpu (By similarity).<ref>PMID:9658129</ref> Capsid protein p24 forms the conical core that encapsulates the genomic RNA-nucleocapsid complex in the virion. Most core are conical, with only 7% tubular. The core is constituted by capsid protein hexamer subunits. The core is disassembled soon after virion entry. Interaction with human PPIA/CYPA protects the virus from restriction by human TRIM5-alpha and from an unknown antiviral activity in human cells. This capsid restriction by TRIM5 is one of the factors which restricts HIV-1 to the human species (By similarity).<ref>PMID:9658129</ref> Nucleocapsid protein p7 encapsulates and protects viral dimeric unspliced (genomic) RNA. Binds these RNAs through its zinc fingers. Facilitates rearangement of nucleic acid secondary structure during retrotranscription of genomic RNA. This capability is referred to as nucleic acid chaperone activity (By similarity).<ref>PMID:9658129</ref> The aspartyl protease mediates proteolytic cleavages of Gag and Gag-Pol polyproteins during or shortly after the release of the virion from the plasma membrane. Cleavages take place as an ordered, step-wise cascade to yield mature proteins. This process is called maturation. Displays maximal activity during the budding process just prior to particle release from the cell. Also cleaves Nef and Vif, probably concomitantly with viral structural proteins on maturation of virus particles (By similarity).<ref>PMID:9658129</ref> Reverse transcriptase/ribonuclease H (RT) is a multifunctional enzyme that converts the viral RNA genome into dsDNA in the cytoplasm, shortly after virus entry into the cell. This enzyme displays a DNA polymerase activity that can copy either DNA or RNA templates, and a ribonuclease H (RNase H) activity that cleaves the RNA strand of RNA-DNA heteroduplexes in a partially processive 3' to 5' endonucleasic mode. Conversion of viral genomic RNA into dsDNA requires many steps. A tRNA(3)-Lys binds to the primer-binding site (PBS) situated at the 5'-end of the viral RNA. RT uses the 3' end of the tRNA primer to perform a short round of RNA-dependent minus-strand DNA synthesis. The reading proceeds through the U5 region and ends after the repeated (R) region which is present at both ends of viral RNA. The portion of the RNA-DNA heteroduplex is digested by the RNase H, resulting in a ssDNA product attached to the tRNA primer. This ssDNA/tRNA hybridizes with the identical R region situated at the 3' end of viral RNA. This template exchange, known as minus-strand DNA strong stop transfer, can be either intra- or intermolecular. RT uses the 3' end of this newly synthesized short ssDNA to perform the RNA-dependent minus-strand DNA synthesis of the whole template. RNase H digests the RNA template except for two polypurine tracts (PPTs) situated at the 5'-end and near the center of the genome. It is not clear if both polymerase and RNase H activities are simultaneous. RNase H probably can proceed both in a polymerase-dependent (RNA cut into small fragments by the same RT performing DNA synthesis) and a polymerase-independent mode (cleavage of remaining RNA fragments by free RTs). Secondly, RT performs DNA-directed plus-strand DNA synthesis using the PPTs that have not been removed by RNase H as primers. PPTs and tRNA primers are then removed by RNase H. The 3' and 5' ssDNA PBS regions hybridize to form a circular dsDNA intermediate. Strand displacement synthesis by RT to the PBS and PPT ends produces a blunt ended, linear dsDNA copy of the viral genome that includes long terminal repeats (LTRs) at both ends (By similarity).<ref>PMID:9658129</ref> Integrase catalyzes viral DNA integration into the host chromosome, by performing a series of DNA cutting and joining reactions. This enzyme activity takes place after virion entry into a cell and reverse transcription of the RNA genome in dsDNA. The first step in the integration process is 3' processing. This step requires a complex comprising the viral genome, matrix protein, Vpr and integrase. This complex is called the pre-integration complex (PIC). The integrase protein removes 2 nucleotides from each 3' end of the viral DNA, leaving recessed CA OH's at the 3' ends. In the second step, the PIC enters cell nucleus. This process is mediated through integrase and Vpr proteins, and allows the virus to infect a non dividing cell. This ability to enter the nucleus is specific of lentiviruses, other retroviruses cannot and rely on cell division to access cell chromosomes. In the third step, termed strand transfer, the integrase protein joins the previously processed 3' ends to the 5' ends of strands of target cellular DNA at the site of integration. The 5'-ends are produced by integrase-catalyzed staggered cuts, 5 bp apart. A Y-shaped, gapped, recombination intermediate results, with the 5'-ends of the viral DNA strands and the 3' ends of target DNA strands remaining unjoined, flanking a gap of 5 bp. The last step is viral DNA integration into host chromosome. This involves host DNA repair synthesis in which the 5 bp gaps between the unjoined strands are filled in and then ligated. Since this process occurs at both cuts flanking the HIV genome, a 5 bp duplication of host DNA is produced at the ends of HIV-1 integration. Alternatively, Integrase may catalyze the excision of viral DNA just after strand transfer, this is termed disintegration (By similarity).<ref>PMID:9658129</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 19:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 3qlh" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 3qlh" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Reverse transcriptase 3D structures\|Reverse transcriptase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
Line 25:		Line 28:
	[[Category: Dulacia guianensis]]		[[Category: Dulacia guianensis]]
	[[Category: Hiv-1]]		[[Category: Hiv-1]]
		+	[[Category: Large Structures]]
	[[Category: Arnold, E]]		[[Category: Arnold, E]]
	[[Category: Bauman, J D]]		[[Category: Bauman, J D]]

OCA at 19:33, 24 January 2018

OCA — Wed, 24 Jan 2018 19:33:24 GMT

←Older revision		Revision as of 19:33, 24 January 2018
Line 19:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 3qlh" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 3qlh" style="background-color:#fffaf0;"></div>
-
-	==See Also==
-	*[[Reverse transcriptase\|Reverse transcriptase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 17:09, 22 March 2017

OCA — Wed, 22 Mar 2017 17:09:06 GMT

←Older revision		Revision as of 17:09, 22 March 2017
Line 1:		Line 1:
		+
	==HIV-1 Reverse Transcriptase in Complex with Manicol at the RNase H Active Site and TMC278 (Rilpivirine) at the NNRTI Binding Pocket==		==HIV-1 Reverse Transcriptase in Complex with Manicol at the RNase H Active Site and TMC278 (Rilpivirine) at the NNRTI Binding Pocket==
	<StructureSection load='3qlh' size='340' side='right' caption='[[3qlh]], [[Resolution\|resolution]] 2.70Å' scene=''>		<StructureSection load='3qlh' size='340' side='right' caption='[[3qlh]], [[Resolution\|resolution]] 2.70Å' scene=''>
Line 5:		Line 6:
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=MNK:(2S)-5,7-DIHYDROXY-9-METHYL-2-(PROP-1-EN-2-YL)-1,2,3,4-TETRAHYDRO-6H-BENZO[7]ANNULEN-6-ONE'>MNK</scene>, <scene name='pdbligand=T27:4-{[4-({4-[(E)-2-CYANOETHENYL]-2,6-DIMETHYLPHENYL}AMINO)PYRIMIDIN-2-YL]AMINO}BENZONITRILE'>T27</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=MNK:(2S)-5,7-DIHYDROXY-9-METHYL-2-(PROP-1-EN-2-YL)-1,2,3,4-TETRAHYDRO-6H-BENZO[7]ANNULEN-6-ONE'>MNK</scene>, <scene name='pdbligand=T27:4-{[4-({4-[(E)-2-CYANOETHENYL]-2,6-DIMETHYLPHENYL}AMINO)PYRIMIDIN-2-YL]AMINO}BENZONITRILE'>T27</scene></td></tr>
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">gag-pol, POL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11678 HIV-1])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">gag-pol, POL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11678 HIV-1])</td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3qlh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qlh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qlh RCSB], [http://www.ebi.ac.uk/pdbsum/3qlh PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3qlh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qlh OCA], [http://pdbe.org/3qlh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3qlh RCSB], [http://www.ebi.ac.uk/pdbsum/3qlh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3qlh ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 17:		Line 18:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 3qlh" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 09:08, 17 June 2015

OCA — Wed, 17 Jun 2015 09:08:30 GMT

←Older revision		Revision as of 09:08, 17 June 2015
Line 2:		Line 2:
	<StructureSection load='3qlh' size='340' side='right' caption='[[3qlh]], [[Resolution\|resolution]] 2.70Å' scene=''>		<StructureSection load='3qlh' size='340' side='right' caption='[[3qlh]], [[Resolution\|resolution]] 2.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3qlh]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Dulacia_guianensis Dulacia guianensis] and [http://en.wikipedia.org/wiki/~~Human_immunodeficiency_virus_type_1_bh10 Human immunodeficiency virus type~~ 1 ~~bh10~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QLH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QLH FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3qlh]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Dulacia_guianensis Dulacia guianensis] and [http://en.wikipedia.org/wiki/Hiv-1 Hiv-1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QLH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QLH FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=MNK:(2S)-5,7-DIHYDROXY-9-METHYL-2-(PROP-1-EN-2-YL)-1,2,3,4-TETRAHYDRO-6H-BENZO[7]ANNULEN-6-ONE'>MNK</scene>, <scene name='pdbligand=T27:4-{[4-({4-[(E)-2-CYANOETHENYL]-2,6-DIMETHYLPHENYL}AMINO)PYRIMIDIN-2-YL]AMINO}BENZONITRILE'>T27</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=MNK:(2S)-5,7-DIHYDROXY-9-METHYL-2-(PROP-1-EN-2-YL)-1,2,3,4-TETRAHYDRO-6H-BENZO[7]ANNULEN-6-ONE'>MNK</scene>, <scene name='pdbligand=T27:4-{[4-({4-[(E)-2-CYANOETHENYL]-2,6-DIMETHYLPHENYL}AMINO)PYRIMIDIN-2-YL]AMINO}BENZONITRILE'>T27</scene></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">gag-pol, POL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11678 ~~Human immunodeficiency virus type~~ 1 ~~BH10~~])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">gag-pol, POL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11678 HIV-1])</td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3qlh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qlh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qlh RCSB], [http://www.ebi.ac.uk/pdbsum/3qlh PDBsum]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3qlh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qlh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qlh RCSB], [http://www.ebi.ac.uk/pdbsum/3qlh PDBsum]</span></td></tr>
	</table>		</table>
Line 25:		Line 25:
	</StructureSection>		</StructureSection>
	[[Category: Dulacia guianensis]]		[[Category: Dulacia guianensis]]
-	[[Category: ~~Human immunodeficiency virus type~~ 1 ~~bh10~~]]	+	[[Category: Hiv-1]]
	[[Category: Arnold, E]]		[[Category: Arnold, E]]
	[[Category: Bauman, J D]]		[[Category: Bauman, J D]]

OCA at 19:51, 25 December 2014

OCA — Thu, 25 Dec 2014 19:51:22 GMT

←Older revision		Revision as of 19:51, 25 December 2014
Line 7:		Line 7:
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3qlh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qlh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qlh RCSB], [http://www.ebi.ac.uk/pdbsum/3qlh PDBsum]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3qlh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qlh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qlh RCSB], [http://www.ebi.ac.uk/pdbsum/3qlh PDBsum]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/POL_HV1B1 POL_HV1B1]] Gag-Pol polyprotein and Gag polyprotein may regulate their own translation, by the binding genomic RNA in the 5'-UTR. At low concentration, Gag-Pol and Gag would promote translation, whereas at high concentration, the polyproteins encapsidate genomic RNA and then shutt off translation (By similarity).<ref>PMID:9658129</ref> Matrix protein p17 has two main functions: in infected cell, it targets Gag and Gag-pol polyproteins to the plasma membrane via a multipartite membrane-binding signal, that includes its myristoylated N-terminus. The second function is to play a role in nuclear localization of the viral genome at the very start of cell infection. Matrix protein is the part of the pre-integration complex. It binds in the cytoplasm the human BAF protein which prevent autointegration of the viral genome, and might be included in virions at the ration of zero to 3 BAF dimer per virion. The myristoylation signal and the NLS thus exert conflicting influences its subcellular localization. The key regulation of these motifs might be phosphorylation of a portion of MA molecules on the C-terminal tyrosine at the time of virus maturation, by virion-associated cellular tyrosine kinase. Implicated in the release from host cell mediated by Vpu (By similarity).<ref>PMID:9658129</ref> Capsid protein p24 forms the conical core that encapsulates the genomic RNA-nucleocapsid complex in the virion. Most core are conical, with only 7% tubular. The core is constituted by capsid protein hexamer subunits. The core is disassembled soon after virion entry. Interaction with human PPIA/CYPA protects the virus from restriction by human TRIM5-alpha and from an unknown antiviral activity in human cells. This capsid restriction by TRIM5 is one of the factors which restricts HIV-1 to the human species (By similarity).<ref>PMID:9658129</ref> Nucleocapsid protein p7 encapsulates and protects viral dimeric unspliced (genomic) RNA. Binds these RNAs through its zinc fingers. Facilitates rearangement of nucleic acid secondary structure during retrotranscription of genomic RNA. This capability is referred to as nucleic acid chaperone activity (By similarity).<ref>PMID:9658129</ref> The aspartyl protease mediates proteolytic cleavages of Gag and Gag-Pol polyproteins during or shortly after the release of the virion from the plasma membrane. Cleavages take place as an ordered, step-wise cascade to yield mature proteins. This process is called maturation. Displays maximal activity during the budding process just prior to particle release from the cell. Also cleaves Nef and Vif, probably concomitantly with viral structural proteins on maturation of virus particles (By similarity).<ref>PMID:9658129</ref> Reverse transcriptase/ribonuclease H (RT) is a multifunctional enzyme that converts the viral RNA genome into dsDNA in the cytoplasm, shortly after virus entry into the cell. This enzyme displays a DNA polymerase activity that can copy either DNA or RNA templates, and a ribonuclease H (RNase H) activity that cleaves the RNA strand of RNA-DNA heteroduplexes in a partially processive 3' to 5' endonucleasic mode. Conversion of viral genomic RNA into dsDNA requires many steps. A tRNA(3)-Lys binds to the primer-binding site (PBS) situated at the 5'-end of the viral RNA. RT uses the 3' end of the tRNA primer to perform a short round of RNA-dependent minus-strand DNA synthesis. The reading proceeds through the U5 region and ends after the repeated (R) region which is present at both ends of viral RNA. The portion of the RNA-DNA heteroduplex is digested by the RNase H, resulting in a ssDNA product attached to the tRNA primer. This ssDNA/tRNA hybridizes with the identical R region situated at the 3' end of viral RNA. This template exchange, known as minus-strand DNA strong stop transfer, can be either intra- or intermolecular. RT uses the 3' end of this newly synthesized short ssDNA to perform the RNA-dependent minus-strand DNA synthesis of the whole template. RNase H digests the RNA template except for two polypurine tracts (PPTs) situated at the 5'-end and near the center of the genome. It is not clear if both polymerase and RNase H activities are simultaneous. RNase H probably can proceed both in a polymerase-dependent (RNA cut into small fragments by the same RT performing DNA synthesis) and a polymerase-independent mode (cleavage of remaining RNA fragments by free RTs). Secondly, RT performs DNA-directed plus-strand DNA synthesis using the PPTs that have not been removed by RNase H as primers. PPTs and tRNA primers are then removed by RNase H. The 3' and 5' ssDNA PBS regions hybridize to form a circular dsDNA intermediate. Strand displacement synthesis by RT to the PBS and PPT ends produces a blunt ended, linear dsDNA copy of the viral genome that includes long terminal repeats (LTRs) at both ends (By similarity).<ref>PMID:9658129</ref> Integrase catalyzes viral DNA integration into the host chromosome, by performing a series of DNA cutting and joining reactions. This enzyme activity takes place after virion entry into a cell and reverse transcription of the RNA genome in dsDNA. The first step in the integration process is 3' processing. This step requires a complex comprising the viral genome, matrix protein, Vpr and integrase. This complex is called the pre-integration complex (PIC). The integrase protein removes 2 nucleotides from each 3' end of the viral DNA, leaving recessed CA OH's at the 3' ends. In the second step, the PIC enters cell nucleus. This process is mediated through integrase and Vpr proteins, and allows the virus to infect a non dividing cell. This ability to enter the nucleus is specific of lentiviruses, other retroviruses cannot and rely on cell division to access cell chromosomes. In the third step, termed strand transfer, the integrase protein joins the previously processed 3' ends to the 5' ends of strands of target cellular DNA at the site of integration. The 5'-ends are produced by integrase-catalyzed staggered cuts, 5 bp apart. A Y-shaped, gapped, recombination intermediate results, with the 5'-ends of the viral DNA strands and the 3' ends of target DNA strands remaining unjoined, flanking a gap of 5 bp. The last step is viral DNA integration into host chromosome. This involves host DNA repair synthesis in which the 5 bp gaps between the unjoined strands are filled in and then ligated. Since this process occurs at both cuts flanking the HIV genome, a 5 bp duplication of host DNA is produced at the ends of HIV-1 integration. Alternatively, Integrase may catalyze the excision of viral DNA just after strand transfer, this is termed disintegration (By similarity).<ref>PMID:9658129</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==

OCA at 13:29, 9 December 2014

OCA — Tue, 09 Dec 2014 13:29:59 GMT

←Older revision		Revision as of 13:29, 9 December 2014
Line 1:		Line 1:
-	[[~~Image:~~3qlh.~~png~~\|~~left~~\|~~200px~~]]	+	==HIV-1 Reverse Transcriptase in Complex with Manicol at the RNase H Active Site and TMC278 (Rilpivirine) at the NNRTI Binding Pocket==
		+	<StructureSection load='3qlh' size='340' side='right' caption='[[3qlh]], [[Resolution\|resolution]] 2.70Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[3qlh]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Dulacia_guianensis Dulacia guianensis] and [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_type_1_bh10 Human immunodeficiency virus type 1 bh10]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QLH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QLH FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=MNK:(2S)-5,7-DIHYDROXY-9-METHYL-2-(PROP-1-EN-2-YL)-1,2,3,4-TETRAHYDRO-6H-BENZO[7]ANNULEN-6-ONE'>MNK</scene>, <scene name='pdbligand=T27:4-{[4-({4-[(E)-2-CYANOETHENYL]-2,6-DIMETHYLPHENYL}AMINO)PYRIMIDIN-2-YL]AMINO}BENZONITRILE'>T27</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">gag-pol, POL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11678 Human immunodeficiency virus type 1 BH10])</td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3qlh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qlh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qlh RCSB], [http://www.ebi.ac.uk/pdbsum/3qlh PDBsum]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The alpha-hydroxytroplone, manicol (5,7-dihydroxy-2-isopropenyl-9-methyl-1,2,3,4-tetrahydro-benzocyclohepten- 6-one), potently and specifically inhibits ribonuclease H (RNase H) activity of human immunodeficiency virus reverse transcriptase (HIV RT) in vitro. However, manicol was ineffective in reducing virus replication in culture. Ongoing efforts to improve the potency and specificity over the lead compound led us to synthesize 14 manicol derivatives that retain the divalent metal-chelating alpha-hydroxytropolone pharmacophore. These efforts were augmented by a high resolution structure of p66/p51 HIV-1 RT containing the nonnucleoside reverse transcriptase inhibitor (NNRTI), TMC278 and manicol in the DNA polymerase and RNase H active sites, respectively. We demonstrate here that several modified alpha-hydroxytropolones exhibit antiviral activity at noncytotoxic concentrations. Inclusion of RNase H active site mutants indicated that manicol analogues can occupy an additional site in or around the DNA polymerase catalytic center. Collectively, our studies will promote future structure-based design of improved alpha-hydroxytropolones to complement the NRTI and NNRTI currently in clinical use.

-	~~{{STRUCTURE_3qlh\| PDB=3qlh \| SCENE= }}~~	+	Synthesis, activity, and structural analysis of novel alpha-hydroxytropolone inhibitors of human immunodeficiency virus reverse transcriptase-associated ribonuclease H.,Chung S, Himmel DM, Jiang JK, Wojtak K, Bauman JD, Rausch JW, Wilson JA, Beutler JA, Thomas CJ, Arnold E, Le Grice SF J Med Chem. 2011 Jul 14;54(13):4462-73. Epub 2011 Jun 2. PMID:21568335<ref>PMID:21568335</ref>

-	~~===HIV-1 Reverse Transcriptase in Complex with Manicol at~~ the ~~RNase H Active Site and TMC278 (Rilpivirine) at the NNRTI Binding Pocket===~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>

-	~~{{ABSTRACT_PUBMED_21568335}}~~	+	==See Also==
-		+	*[[Reverse transcriptase\|Reverse transcriptase]]
-	==~~About this Structure~~==	+	== References ==
-	[[~~3qlh~~]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Dulacia_guianensis Dulacia guianensis] and [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_type_1_bh10 Human immunodeficiency virus type 1 bh10]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QLH OCA].	+	<references/>
-		+	__TOC__
-	==~~Reference~~==	+	</StructureSection>
-	<~~ref group="xtra">PMID:021568335<~~/~~ref~~><~~ref group="xtra">PMID:020004166</ref><ref group="xtra">PMID:018676450</ref><references group="xtra"~~/>	+
	[[Category: Dulacia guianensis]]		[[Category: Dulacia guianensis]]
	[[Category: Human immunodeficiency virus type 1 bh10]]		[[Category: Human immunodeficiency virus type 1 bh10]]
-	[[Category: Arnold, E.]]	+	[[Category: Arnold, E]]
-	[[Category: Bauman, J D.]]	+	[[Category: Bauman, J D]]
-	[[Category: Himmel, D M.]]	+	[[Category: Himmel, D M]]
-	[[Category: Wojtak, K.]]	+	[[Category: Wojtak, K]]
	[[Category: Divalent cation chelator]]		[[Category: Divalent cation chelator]]
	[[Category: Hydrolase-inhibitor complex]]		[[Category: Hydrolase-inhibitor complex]]

OCA at 13:30, 27 February 2013

OCA — Wed, 27 Feb 2013 13:30:16 GMT

←Older revision		Revision as of 13:30, 27 February 2013
Line 8:		Line 8:

	==About this Structure==		==About this Structure==
-	[[3qlh]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Dulacia_guianensis Dulacia guianensis] and [http://en.wikipedia.org/wiki/~~Human_immunodeficiency_virus_1~~ Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QLH OCA].	+	[[3qlh]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Dulacia_guianensis Dulacia guianensis] and [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_type_1_bh10 Human immunodeficiency virus type 1 bh10]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QLH OCA].

	==Reference==		==Reference==
	<ref group="xtra">PMID:021568335</ref><ref group="xtra">PMID:020004166</ref><ref group="xtra">PMID:018676450</ref><references group="xtra"/>		<ref group="xtra">PMID:021568335</ref><ref group="xtra">PMID:020004166</ref><ref group="xtra">PMID:018676450</ref><references group="xtra"/>
	[[Category: Dulacia guianensis]]		[[Category: Dulacia guianensis]]
-	[[Category: Human immunodeficiency virus 1]]	+	[[Category: Human immunodeficiency virus type 1 bh10]]
	[[Category: Arnold, E.]]		[[Category: Arnold, E.]]
	[[Category: Bauman, J D.]]		[[Category: Bauman, J D.]]

OCA at 04:43, 18 July 2012

OCA — Wed, 18 Jul 2012 04:43:42 GMT

←Older revision		Revision as of 04:43, 18 July 2012
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	[[Image:3qlh.png\|left\|200px]]

-	~~The entry~~ 3qlh ~~is ON HOLD~~ ~~until Paper Publication~~	+	{{STRUCTURE_3qlh\| PDB=3qlh \| SCENE= }}

-	~~Authors: Himmel, D.M., Wojak, K., Bauman, J.D., Arnold, E.~~	+	===HIV-1 Reverse Transcriptase in Complex with Manicol at the RNase H Active Site and TMC278 (Rilpivirine) at the NNRTI Binding Pocket===

-	~~Description~~: ~~HIV~~-1 ~~Reverse Transcriptase in Complex with Manicol at the RNase H Active Site and TMC278 (Rilpilvirine) at the NNRTI Binding Pocket~~	+	{{ABSTRACT_PUBMED_21568335}}
		+
		+	==About this Structure==
		+	[[3qlh]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Dulacia_guianensis Dulacia guianensis] and [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QLH OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:021568335</ref><ref group="xtra">PMID:020004166</ref><ref group="xtra">PMID:018676450</ref><references group="xtra"/>
		+	[[Category: Dulacia guianensis]]
		+	[[Category: Human immunodeficiency virus 1]]
		+	[[Category: Arnold, E.]]
		+	[[Category: Bauman, J D.]]
		+	[[Category: Himmel, D M.]]
		+	[[Category: Wojtak, K.]]
		+	[[Category: Divalent cation chelator]]
		+	[[Category: Hydrolase-inhibitor complex]]
		+	[[Category: Non-nucleoside rt inhibitor]]
		+	[[Category: Rnase h inhibitor]]
		+	[[Category: Structure-based drug design]]
		+	[[Category: Transferase]]
		+	[[Category: Tropolone derivative]]

OCA at 05:22, 16 February 2011

OCA — Wed, 16 Feb 2011 05:22:00 GMT

←Older revision		Revision as of 05:22, 16 February 2011
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 3qlh is ON HOLD	+	The entry 3qlh is ON HOLD until Paper Publication

	Authors: Himmel, D.M., Wojak, K., Bauman, J.D., Arnold, E.		Authors: Himmel, D.M., Wojak, K., Bauman, J.D., Arnold, E.

	Description: HIV-1 Reverse Transcriptase in Complex with Manicol at the RNase H Active Site and TMC278 (Rilpilvirine) at the NNRTI Binding Pocket		Description: HIV-1 Reverse Transcriptase in Complex with Manicol at the RNase H Active Site and TMC278 (Rilpilvirine) at the NNRTI Binding Pocket