3t19 - Revision history

OCA at 13:14, 14 March 2024

OCA — Thu, 14 Mar 2024 13:14:16 GMT

←Older revision		Revision as of 13:14, 14 March 2024
Line 3:		Line 3:
	<StructureSection load='3t19' size='340' side='right'caption='[[3t19]], [[Resolution\|resolution]] 2.60Å' scene=''>		<StructureSection load='3t19' size='340' side='right'caption='[[3t19]], [[Resolution\|resolution]] 2.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3t19]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Hiv~~-~~1 Hiv~~-1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T19 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3T19 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3t19]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/HIV-1_M:B_HXB2R HIV-1 M:B_HXB2R]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T19 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3T19 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5MA:1-(2,5-DICHLORO-3-{[5-CHLORO-1-(2H-PYRAZOLO[3,4-B]PYRIDIN-3-YLMETHYL)-1H-BENZOTRIAZOL-4-YL]OXY}PHENYL)METHANAMINE'>5MA</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]] 2.6Å</td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3t1a\|3t1a]], [[3tam\|3tam]]</div></td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5MA:1-(2,5-DICHLORO-3-{[5-CHLORO-1-(2H-PYRAZOLO[3,4-B]PYRIDIN-3-YLMETHYL)-1H-BENZOTRIAZOL-4-YL]OXY}PHENYL)METHANAMINE'>5MA</scene></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">gag-pol, HIV-1 POL ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11706 HIV-1])~~</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=3t19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t19 OCA], [https://pdbe.org/3t19 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3t19 RCSB], [https://www.ebi.ac.uk/pdbsum/3t19 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3t19 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=3t19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t19 OCA], [https://pdbe.org/3t19 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3t19 RCSB], [https://www.ebi.ac.uk/pdbsum/3t19 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3t19 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/POL_HV1H2 POL_HV1H2]] 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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</ref>	+	[https://www.uniprot.org/uniprot/POL_HV1H2 POL_HV1H2] 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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Highly active anti-retroviral therapy (HAART) significantly reduces HIV viral load and has led to a dramatic decrease in AIDS related mortality. Despite this success, there remains a critical need for new HIV therapies to address the emergence of drug resistant viral strains. Next generation NNRTIs are sought which are effective against these mutant forms of the HIV virus. The bound conformations of our lead inhibitors, MK-1107 (1) and MK-4965 (2), were divergent about the oxymethylene linker and each of these conformations were rigidified using two isomeric cyclic constraints. The constraint derived from the bioactive conformation of 2 provided novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Systematic SAR led to the identification of indazole as the optimal conformational constraint to provide MK-6186 (3) and MK-7445 (6). Despite their reduced flexibility, these compounds had comparable potency to the corresponding acyclic ethers in both recombinant enzyme and cell based assays against both the wild-type (wt) and the clinically relevant mutant strains.	+
-		+
-	Design and Synthesis of conformationally Constrained Inhibitors of Non-Nucleoside Reverse Transcriptase.,Gomez R, Jolly S, Williams TM, Vacca JP, Torrent M, McGaughey G, Lai MT, Felock PJ, Munshi V, Distefano D, Flynn JA, Miller MD, Yan Y, Reid JC, Sanchez R, Liang Y, Paton B, Wan BL, Anthony NJ J Med Chem. 2011 Oct 10. PMID:21985673<ref>PMID:21985673</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 3t19" style="background-color:#fffaf0;"></div~~>	+

	==See Also==		==See Also==
Line 27:		Line 17:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Hiv~~-1]]	+	[[Category: HIV-1 M:B_HXB2R]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Reid, J]]	+	[[Category: Reid J]]
-	[[Category: Yan, Y]]	+	[[Category: Yan Y]]
-	~~[[Category: Hiv-1 reverse transcriptase]]~~	+
-	~~[[Category: Non-nucleoside inhibition]]~~	+
-	~~[[Category: Nucleotidyltrasferase]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 16:38, 6 July 2022

OCA — Wed, 06 Jul 2022 16:38:51 GMT

←Older revision		Revision as of 16:38, 6 July 2022
Line 1:		Line 1:

	==Crystal structure of HIV-1 reverse transcriptase (wild type) in complex with inhibitor M05==		==Crystal structure of HIV-1 reverse transcriptase (wild type) in complex with inhibitor M05==
-	<StructureSection load='3t19' size='340' side='right' caption='[[3t19]], [[Resolution\|resolution]] 2.60Å' scene=''>	+	<StructureSection load='3t19' size='340' side='right'caption='[[3t19]], [[Resolution\|resolution]] 2.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3t19]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/Hiv-1 Hiv-1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T19 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3T19 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3t19]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Hiv-1 Hiv-1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T19 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3T19 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5MA:1-(2,5-DICHLORO-3-{[5-CHLORO-1-(2H-PYRAZOLO[3,4-B]PYRIDIN-3-YLMETHYL)-1H-BENZOTRIAZOL-4-YL]OXY}PHENYL)METHANAMINE'>5MA</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5MA:1-(2,5-DICHLORO-3-{[5-CHLORO-1-(2H-PYRAZOLO[3,4-B]PYRIDIN-3-YLMETHYL)-1H-BENZOTRIAZOL-4-YL]OXY}PHENYL)METHANAMINE'>5MA</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3t1a\|3t1a]], [[3tam\|3tam]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3t1a\|3t1a]], [[3tam\|3tam]]</div></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">gag-pol, HIV-1 POL ([~~http~~://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11706 HIV-1])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">gag-pol, HIV-1 POL ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11706 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=3t19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t19 OCA], [~~http~~://pdbe.org/3t19 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3t19 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3t19 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3t19 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=3t19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t19 OCA], [https://pdbe.org/3t19 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3t19 RCSB], [https://www.ebi.ac.uk/pdbsum/3t19 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3t19 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/POL_HV1H2 POL_HV1H2]] 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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</ref>	+	[[https://www.uniprot.org/uniprot/POL_HV1H2 POL_HV1H2]] 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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 22:		Line 22:

	==See Also==		==See Also==
-	*[[Reverse transcriptase\|Reverse transcriptase]]	+	*[[Reverse transcriptase 3D structures\|Reverse transcriptase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
Line 28:		Line 28:
	</StructureSection>		</StructureSection>
	[[Category: Hiv-1]]		[[Category: Hiv-1]]
		+	[[Category: Large Structures]]
	[[Category: Reid, J]]		[[Category: Reid, J]]
	[[Category: Yan, Y]]		[[Category: Yan, Y]]

OCA at 15:20, 5 August 2016

OCA — Fri, 05 Aug 2016 15:20:00 GMT

←Older revision		Revision as of 15:20, 5 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of HIV-1 reverse transcriptase (wild type) in complex with inhibitor M05==		==Crystal structure of HIV-1 reverse transcriptase (wild type) in complex with inhibitor M05==
	<StructureSection load='3t19' size='340' side='right' caption='[[3t19]], [[Resolution\|resolution]] 2.60Å' scene=''>		<StructureSection load='3t19' size='340' side='right' caption='[[3t19]], [[Resolution\|resolution]] 2.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3t19]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hiv-~~1_m:b_hxb2r~~ Hiv-1 ~~m:b_hxb2r~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T19 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3T19 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3t19]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hiv-1 Hiv-1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T19 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3T19 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5MA:1-(2,5-DICHLORO-3-{[5-CHLORO-1-(2H-PYRAZOLO[3,4-B]PYRIDIN-3-YLMETHYL)-1H-BENZOTRIAZOL-4-YL]OXY}PHENYL)METHANAMINE'>5MA</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5MA:1-(2,5-DICHLORO-3-{[5-CHLORO-1-(2H-PYRAZOLO[3,4-B]PYRIDIN-3-YLMETHYL)-1H-BENZOTRIAZOL-4-YL]OXY}PHENYL)METHANAMINE'>5MA</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3t1a\|3t1a]], [[3tam\|3tam]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3t1a\|3t1a]], [[3tam\|3tam]]</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">gag-pol, HIV-1 POL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11706 HIV-1 ~~M:B_HXB2R~~])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">gag-pol, HIV-1 POL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11706 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=3t19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t19 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3t19 RCSB], [http://www.ebi.ac.uk/pdbsum/3t19 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=3t19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t19 OCA], [http://pdbe.org/3t19 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3t19 RCSB], [http://www.ebi.ac.uk/pdbsum/3t19 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3t19 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 19:
	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 3t19" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 25:		Line 27:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Hiv-1 ~~m:b_hxb2r~~]]	+	[[Category: Hiv-1]]
	[[Category: Reid, J]]		[[Category: Reid, J]]
	[[Category: Yan, Y]]		[[Category: Yan, Y]]
-	[[Category: Hiv-1]]
	[[Category: Hiv-1 reverse transcriptase]]		[[Category: Hiv-1 reverse transcriptase]]
	[[Category: Non-nucleoside inhibition]]		[[Category: Non-nucleoside inhibition]]
	[[Category: Nucleotidyltrasferase]]		[[Category: Nucleotidyltrasferase]]
	[[Category: Transferase-transferase inhibitor complex]]		[[Category: Transferase-transferase inhibitor complex]]

OCA at 19:52, 25 December 2014

OCA — Thu, 25 Dec 2014 19:52:54 GMT

←Older revision		Revision as of 19:52, 25 December 2014
Line 8:		Line 8:
	<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=3t19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t19 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3t19 RCSB], [http://www.ebi.ac.uk/pdbsum/3t19 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=3t19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t19 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3t19 RCSB], [http://www.ebi.ac.uk/pdbsum/3t19 PDBsum]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/POL_HV1H2 POL_HV1H2]] 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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</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.<ref>PMID:8648689</ref> <ref>PMID:17041220</ref> <ref>PMID:17070549</ref> <ref>PMID:20554775</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==

OCA at 13:36, 9 December 2014

OCA — Tue, 09 Dec 2014 13:36:42 GMT

←Older revision		Revision as of 13:36, 9 December 2014
Line 1:		Line 1:
-	[[~~Image:~~3t19.~~png~~\|~~left~~\|~~200px~~]]	+	==Crystal structure of HIV-1 reverse transcriptase (wild type) in complex with inhibitor M05==
		+	<StructureSection load='3t19' size='340' side='right' caption='[[3t19]], [[Resolution\|resolution]] 2.60Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[3t19]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hiv-1_m:b_hxb2r Hiv-1 m:b_hxb2r]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T19 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3T19 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5MA:1-(2,5-DICHLORO-3-{[5-CHLORO-1-(2H-PYRAZOLO[3,4-B]PYRIDIN-3-YLMETHYL)-1H-BENZOTRIAZOL-4-YL]OXY}PHENYL)METHANAMINE'>5MA</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3t1a\|3t1a]], [[3tam\|3tam]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">gag-pol, HIV-1 POL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11706 HIV-1 M:B_HXB2R])</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=3t19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t19 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3t19 RCSB], [http://www.ebi.ac.uk/pdbsum/3t19 PDBsum]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Highly active anti-retroviral therapy (HAART) significantly reduces HIV viral load and has led to a dramatic decrease in AIDS related mortality. Despite this success, there remains a critical need for new HIV therapies to address the emergence of drug resistant viral strains. Next generation NNRTIs are sought which are effective against these mutant forms of the HIV virus. The bound conformations of our lead inhibitors, MK-1107 (1) and MK-4965 (2), were divergent about the oxymethylene linker and each of these conformations were rigidified using two isomeric cyclic constraints. The constraint derived from the bioactive conformation of 2 provided novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Systematic SAR led to the identification of indazole as the optimal conformational constraint to provide MK-6186 (3) and MK-7445 (6). Despite their reduced flexibility, these compounds had comparable potency to the corresponding acyclic ethers in both recombinant enzyme and cell based assays against both the wild-type (wt) and the clinically relevant mutant strains.

-	~~{{STRUCTURE_3t19\| PDB=3t19 \| SCENE= }}~~	+	Design and Synthesis of conformationally Constrained Inhibitors of Non-Nucleoside Reverse Transcriptase.,Gomez R, Jolly S, Williams TM, Vacca JP, Torrent M, McGaughey G, Lai MT, Felock PJ, Munshi V, Distefano D, Flynn JA, Miller MD, Yan Y, Reid JC, Sanchez R, Liang Y, Paton B, Wan BL, Anthony NJ J Med Chem. 2011 Oct 10. PMID:21985673<ref>PMID:21985673</ref>

-	~~===Crystal structure~~ of ~~HIV-1 reverse transcriptase (wild type) in complex with inhibitor M05===~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~{{ABSTRACT_PUBMED_21985673}}~~	+
-		+
-	~~==About this Structure==~~	+
-	~~[[3t19]] is a 2 chain structure with sequence from [http://en~~.~~wikipedia~~.~~org/wiki/Hiv-1_m:b_hxb2r Hiv-1 m:b_hxb2r]~~. ~~Full crystallographic information is available from [http:~~/~~/oca.weizmann.ac.il/oca-bin/ocashort?id=3T19 OCA].~~	+

	==See Also==		==See Also==
	*[[Reverse transcriptase\|Reverse transcriptase]]		*[[Reverse transcriptase\|Reverse transcriptase]]
-		+	== References ==
-	==~~Reference~~==	+	<references/>
-	<~~ref group="xtra">PMID:021985673<~~/~~ref~~><~~references group="xtra"~~/>	+	__TOC__
		+	</StructureSection>
	[[Category: Hiv-1 m:b_hxb2r]]		[[Category: Hiv-1 m:b_hxb2r]]
-	[[Category: Reid, J.]]	+	[[Category: Reid, J]]
-	[[Category: Yan, Y.]]	+	[[Category: Yan, Y]]
	[[Category: Hiv-1]]		[[Category: Hiv-1]]
	[[Category: Hiv-1 reverse transcriptase]]		[[Category: Hiv-1 reverse transcriptase]]

OCA at 20:47, 20 October 2012

OCA — Sat, 20 Oct 2012 20:47:15 GMT

←Older revision		Revision as of 20:47, 20 October 2012
Line 8:		Line 8:

	==About this Structure==		==About this Structure==
-	[[3t19]] is a 2 chain structure ~~of [[Reverse transcriptase]]~~ with sequence from [http://en.wikipedia.org/wiki/Hiv-1_m:b_hxb2r Hiv-1 m:b_hxb2r]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T19 OCA].	+	[[3t19]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hiv-1_m:b_hxb2r Hiv-1 m:b_hxb2r]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T19 OCA].

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

OCA at 11:36, 27 July 2012

OCA — Fri, 27 Jul 2012 11:36:56 GMT

←Older revision		Revision as of 11:36, 27 July 2012
Line 1:		Line 1:
	[[Image:3t19.png\|left\|200px]]		[[Image:3t19.png\|left\|200px]]

-	<!--
-	The line below this paragraph, containing "STRUCTURE_3t19", creates the "Structure Box" on the page.
-	You may change the PDB parameter (which sets the PDB file loaded into the applet)
-	or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-	or leave the SCENE parameter empty for the default display.
-	-->
	{{STRUCTURE_3t19\| PDB=3t19 \| SCENE= }}		{{STRUCTURE_3t19\| PDB=3t19 \| SCENE= }}

	===Crystal structure of HIV-1 reverse transcriptase (wild type) in complex with inhibitor M05===		===Crystal structure of HIV-1 reverse transcriptase (wild type) in complex with inhibitor M05===

-
-	<!--
-	The line below this paragraph, {{ABSTRACT_PUBMED_21985673}}, adds the Publication Abstract to the page
-	(as it appears on PubMed at http://www.pubmed.gov), where 21985673 is the PubMed ID number.
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	{{ABSTRACT_PUBMED_21985673}}		{{ABSTRACT_PUBMED_21985673}}

Line 22:		Line 11:

	==See Also==		==See Also==
-	*[[Reverse transcriptase]]	+	*[[Reverse transcriptase\|Reverse transcriptase]]

	==Reference==		==Reference==

OCA at 06:06, 1 February 2012

OCA — Wed, 01 Feb 2012 06:06:53 GMT

←Older revision		Revision as of 06:06, 1 February 2012
Line 19:		Line 19:

	==About this Structure==		==About this Structure==
-	[[3t19]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hiv-1_m:b_hxb2r Hiv-1 m:b_hxb2r]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T19 OCA].	+	[[3t19]] is a 2 chain structure of [[Reverse transcriptase]] with sequence from [http://en.wikipedia.org/wiki/Hiv-1_m:b_hxb2r Hiv-1 m:b_hxb2r]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T19 OCA].
		+
		+	==See Also==
		+	*[[Reverse transcriptase]]

	==Reference==		==Reference==

OCA at 09:18, 30 October 2011

OCA — Sun, 30 Oct 2011 09:18:28 GMT

←Older revision		Revision as of 09:18, 30 October 2011
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	[[Image:3t19.png\|left\|200px]]

-	The ~~entry 3t19~~ is ~~ON HOLD~~ ~~until Paper Publication~~	+	<!--
		+	The line below this paragraph, containing "STRUCTURE_3t19", creates the "Structure Box" on the page.
		+	You may change the PDB parameter (which sets the PDB file loaded into the applet)
		+	or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
		+	or leave the SCENE parameter empty for the default display.
		+	-->
		+	{{STRUCTURE_3t19\| PDB=3t19 \| SCENE= }}

-	~~Authors: Yan, Y., Reid, J.~~	+	===Crystal structure of HIV-1 reverse transcriptase (wild type) in complex with inhibitor M05===

-	~~Description~~: ~~Crystal~~ structure ~~of HIV~~-1 reverse transcriptase ~~(wild type) in complex with~~ inhibitor ~~M05~~	+
		+	<!--
		+	The line below this paragraph, {{ABSTRACT_PUBMED_21985673}}, adds the Publication Abstract to the page
		+	(as it appears on PubMed at http://www.pubmed.gov), where 21985673 is the PubMed ID number.
		+	-->
		+	{{ABSTRACT_PUBMED_21985673}}
		+
		+	==About this Structure==
		+	[[3t19]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hiv-1_m:b_hxb2r Hiv-1 m:b_hxb2r]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T19 OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:021985673</ref><references group="xtra"/>
		+	[[Category: Hiv-1 m:b_hxb2r]]
		+	[[Category: Reid, J.]]
		+	[[Category: Yan, Y.]]
		+	[[Category: Hiv-1]]
		+	[[Category: Hiv-1 reverse transcriptase]]
		+	[[Category: Non-nucleoside inhibition]]
		+	[[Category: Nucleotidyltrasferase]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 06:20, 31 August 2011

OCA — Wed, 31 Aug 2011 06:20:12 GMT

←Older revision		Revision as of 06:20, 31 August 2011
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 3t19 is ON HOLD	+	The entry 3t19 is ON HOLD until Paper Publication

	Authors: Yan, Y., Reid, J.		Authors: Yan, Y., Reid, J.

	Description: Crystal structure of HIV-1 reverse transcriptase (wild type) in complex with inhibitor M05		Description: Crystal structure of HIV-1 reverse transcriptase (wild type) in complex with inhibitor M05