4ztj - Revision history

OCA at 12:16, 6 March 2024

OCA — Wed, 06 Mar 2024 12:16:51 GMT

←Older revision		Revision as of 12:16, 6 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4ztj]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_spumaretrovirus Human spumaretrovirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZTJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZTJ FirstGlance]. <br>		<table><tr><td colspan='2'>[[4ztj]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_spumaretrovirus Human spumaretrovirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZTJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZTJ FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4RT:(1R,2S,5R)-8-(3-CHLORO-4-FLUOROBENZYL)-6-HYDROXY-1-(HYDROXYMETHYL)-2-METHYL-9,10-DIHYDRO-2H-SPIRO[BICYCLO[3.1.0]HEXANE-2,3-IMIDAZO[5,1-A][2,6]NAPHTHYRIDINE]-1,5,7(8H)-TRIONE'>4RT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.67Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4RT:(1R,2S,5R)-8-(3-CHLORO-4-FLUOROBENZYL)-6-HYDROXY-1-(HYDROXYMETHYL)-2-METHYL-9,10-DIHYDRO-2H-SPIRO[BICYCLO[3.1.0]HEXANE-2,3-IMIDAZO[5,1-A][2,6]NAPHTHYRIDINE]-1,5,7(8H)-TRIONE'>4RT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=4ztj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ztj OCA], [https://pdbe.org/4ztj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ztj RCSB], [https://www.ebi.ac.uk/pdbsum/4ztj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ztj 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=4ztj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ztj OCA], [https://pdbe.org/4ztj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ztj RCSB], [https://www.ebi.ac.uk/pdbsum/4ztj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ztj ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/POL_FOAMV POL_FOAMV] The aspartyl protease activity mediates proteolytic cleavages of Gag and Pol polyproteins. The reverse transcriptase (RT) activity converts the viral RNA genome into dsDNA in the cytoplasm, shortly after virus entry into the cell (early reverse transcription) or after proviral DNA transcription (late reverse transcription). RT consists of 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-Lys1,2 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 a polypurine tract (PPT) 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 PPT that has not been removed by RNase H as primer. PPT 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). 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 at least the viral genome, matrix protein, and integrase. This complex is called the pre-integration complex (PIC). The integrase protein removes 2 nucleotides from the 3' end of the viral DNA right (U5) end, leaving the left (U3) intact. In the second step, the PIC enters cell nucleus. This process is mediated through the integrase and allows the virus to infect both dividing (nuclear membrane disassembled) and G1/S-arrested cells (active translocation), but with no viral gene expression in the latter. 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. It is however not clear how integration then proceeds to resolve the asymmetrical cleavage of viral DNA (By similarity).		[https://www.uniprot.org/uniprot/POL_FOAMV POL_FOAMV] The aspartyl protease activity mediates proteolytic cleavages of Gag and Pol polyproteins. The reverse transcriptase (RT) activity converts the viral RNA genome into dsDNA in the cytoplasm, shortly after virus entry into the cell (early reverse transcription) or after proviral DNA transcription (late reverse transcription). RT consists of 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-Lys1,2 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 a polypurine tract (PPT) 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 PPT that has not been removed by RNase H as primer. PPT 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). 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 at least the viral genome, matrix protein, and integrase. This complex is called the pre-integration complex (PIC). The integrase protein removes 2 nucleotides from the 3' end of the viral DNA right (U5) end, leaving the left (U3) intact. In the second step, the PIC enters cell nucleus. This process is mediated through the integrase and allows the virus to infect both dividing (nuclear membrane disassembled) and G1/S-arrested cells (active translocation), but with no viral gene expression in the latter. 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. It is however not clear how integration then proceeds to resolve the asymmetrical cleavage of viral DNA (By similarity).
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	The search for new molecular constructs that resemble the critical 2-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetics to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules.
-
-	Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors.,Raheem I, Walji A, Klein D, Sanders JM, Powell D, Abeywickrema P, Barbe G, Bennet A, Clas SD, Dubost D, Embrey M, Grobler J, Hafey M, Hartingh TJ, Hazuda DJ, Miller MD, Moore KP, Pajkovic N, Patel S, Rada V, Rearden P, Schreier JD, Sisko J, Steele TG, Truchon JF, Wai J, Xu M, Coleman PJ J Med Chem. 2015 Sep 23. PMID:26397965<ref>PMID:26397965</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 4ztj" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
	*[[Retroviral integrase 3D structures\|Retroviral integrase 3D structures]]		*[[Retroviral integrase 3D structures\|Retroviral integrase 3D structures]]
-	== References ==
-	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 07:41, 18 May 2023

OCA — Thu, 18 May 2023 07:41:05 GMT

←Older revision		Revision as of 07:41, 18 May 2023
Line 3:		Line 3:
	<StructureSection load='4ztj' size='340' side='right'caption='[[4ztj]], [[Resolution\|resolution]] 2.67Å' scene=''>		<StructureSection load='4ztj' size='340' side='right'caption='[[4ztj]], [[Resolution\|resolution]] 2.67Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4ztj]] is a 4 chain structure with sequence from [~~http://en.wikipedia.org/wiki/ ] and [http~~://en.wikipedia.org/wiki/~~Foamv Foamv~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZTJ OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4ZTJ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4ztj]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_spumaretrovirus Human spumaretrovirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZTJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZTJ FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4RT:(1R,2S,5R)-8-(3-CHLORO-4-FLUOROBENZYL)-6-HYDROXY-1-(HYDROXYMETHYL)-2-METHYL-9,10-DIHYDRO-2H-SPIRO[BICYCLO[3.1.0]HEXANE-2,3-IMIDAZO[5,1-A][2,6]NAPHTHYRIDINE]-1,5,7(8H)-TRIONE'>4RT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>~~</td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4RT:(1R,2S,5R)-8-(3-CHLORO-4-FLUOROBENZYL)-6-HYDROXY-1-(HYDROXYMETHYL)-2-METHYL-9,10-DIHYDRO-2H-SPIRO[BICYCLO[3.1.0]HEXANE-2,3-IMIDAZO[5,1-A][2,6]NAPHTHYRIDINE]-1,5,7(8H)-TRIONE'>4RT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ztf\|4ztf]]</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=4ztj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ztj OCA], [https://pdbe.org/4ztj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ztj RCSB], [https://www.ebi.ac.uk/pdbsum/4ztj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ztj ProSAT]</span></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">pol ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11963 FOAMV])~~</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=4ztj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ztj OCA], [~~http~~://pdbe.org/4ztj PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4ztj RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4ztj PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4ztj ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/POL_FOAMV POL_FOAMV]] The aspartyl protease activity mediates proteolytic cleavages of Gag and Pol polyproteins. The reverse transcriptase (RT) activity converts the viral RNA genome into dsDNA in the cytoplasm, shortly after virus entry into the cell (early reverse transcription) or after proviral DNA transcription (late reverse transcription). RT consists of 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-Lys1,2 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 a polypurine tract (PPT) 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 PPT that has not been removed by RNase H as primer. PPT 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). 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 at least the viral genome, matrix protein, and integrase. This complex is called the pre-integration complex (PIC). The integrase protein removes 2 nucleotides from the 3' end of the viral DNA right (U5) end, leaving the left (U3) intact. In the second step, the PIC enters cell nucleus. This process is mediated through the integrase and allows the virus to infect both dividing (nuclear membrane disassembled) and G1/S-arrested cells (active translocation), but with no viral gene expression in the latter. 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. It is however not clear how integration then proceeds to resolve the asymmetrical cleavage of viral DNA (By similarity).	+	[https://www.uniprot.org/uniprot/POL_FOAMV POL_FOAMV] The aspartyl protease activity mediates proteolytic cleavages of Gag and Pol polyproteins. The reverse transcriptase (RT) activity converts the viral RNA genome into dsDNA in the cytoplasm, shortly after virus entry into the cell (early reverse transcription) or after proviral DNA transcription (late reverse transcription). RT consists of 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-Lys1,2 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 a polypurine tract (PPT) 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 PPT that has not been removed by RNase H as primer. PPT 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). 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 at least the viral genome, matrix protein, and integrase. This complex is called the pre-integration complex (PIC). The integrase protein removes 2 nucleotides from the 3' end of the viral DNA right (U5) end, leaving the left (U3) intact. In the second step, the PIC enters cell nucleus. This process is mediated through the integrase and allows the virus to infect both dividing (nuclear membrane disassembled) and G1/S-arrested cells (active translocation), but with no viral gene expression in the latter. 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. It is however not clear how integration then proceeds to resolve the asymmetrical cleavage of viral DNA (By similarity).
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 22:		Line 20:

	==See Also==		==See Also==
-	*[[Retroviral ~~Integrase~~\|Retroviral ~~Integrase~~]]	+	*[[Retroviral integrase 3D structures\|Retroviral integrase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Foamv~~]]	+	[[Category: Human spumaretrovirus]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Klein~~, D J~~]]	+	[[Category: Klein DJ]]
-	[[Category: Patel, S]]	+	[[Category: Patel S]]
-	~~[[Category: Dna integration]]~~	+
-	~~[[Category: Recombination-inhibitor-dna complex]]~~	+
-	~~[[Category: Transferase-dna complex]]~~	+
-	~~[[Category: Transferase-dna-inhibitor complex]]~~	+
-	~~[[Category: Viral protein~~]]	+

OCA at 08:10, 26 June 2019

OCA — Wed, 26 Jun 2019 08:10:42 GMT

←Older revision		Revision as of 08:10, 26 June 2019
Line 1:		Line 1:
		+
	==Crystal Structure of the Prototype Foamy Virus Intasome with a 2-Pyridinone Aminal Inhibitor==		==Crystal Structure of the Prototype Foamy Virus Intasome with a 2-Pyridinone Aminal Inhibitor==
-	<StructureSection load='4ztj' size='340' side='right' caption='[[4ztj]], [[Resolution\|resolution]] 2.67Å' scene=''>	+	<StructureSection load='4ztj' size='340' side='right'caption='[[4ztj]], [[Resolution\|resolution]] 2.67Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4ztj]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZTJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZTJ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4ztj]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Foamv Foamv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZTJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZTJ FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4RT:(1R,2S,5R)-8-(3-CHLORO-4-FLUOROBENZYL)-6-HYDROXY-1-(HYDROXYMETHYL)-2-METHYL-9,10-DIHYDRO-2H-SPIRO[BICYCLO[3.1.0]HEXANE-2,3-IMIDAZO[5,1-A][2,6]NAPHTHYRIDINE]-1,5,7(8H)-TRIONE'>4RT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4RT:(1R,2S,5R)-8-(3-CHLORO-4-FLUOROBENZYL)-6-HYDROXY-1-(HYDROXYMETHYL)-2-METHYL-9,10-DIHYDRO-2H-SPIRO[BICYCLO[3.1.0]HEXANE-2,3-IMIDAZO[5,1-A][2,6]NAPHTHYRIDINE]-1,5,7(8H)-TRIONE'>4RT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ztf\|4ztf]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ztf\|4ztf]]</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=4ztj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ztj OCA], [http://pdbe.org/4ztj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ztj RCSB], [http://www.ebi.ac.uk/pdbsum/4ztj PDBsum]</span></td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">pol ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11963 FOAMV])</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=4ztj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ztj OCA], [http://pdbe.org/4ztj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ztj RCSB], [http://www.ebi.ac.uk/pdbsum/4ztj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ztj ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 20:
	</div>		</div>
	<div class="pdbe-citations 4ztj" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4ztj" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Retroviral Integrase\|Retroviral Integrase]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Foamv]]
		+	[[Category: Large Structures]]
	[[Category: Klein, D J]]		[[Category: Klein, D J]]
	[[Category: Patel, S]]		[[Category: Patel, S]]

OCA at 13:41, 7 October 2015

OCA — Wed, 07 Oct 2015 13:41:26 GMT

←Older revision		Revision as of 13:41, 7 October 2015
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==Crystal Structure of the Prototype Foamy Virus Intasome with a 2-Pyridinone Aminal Inhibitor==
		+	<StructureSection load='4ztj' size='340' side='right' caption='[[4ztj]], [[Resolution\|resolution]] 2.67Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4ztj]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZTJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZTJ FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4RT:(1R,2S,5R)-8-(3-CHLORO-4-FLUOROBENZYL)-6-HYDROXY-1-(HYDROXYMETHYL)-2-METHYL-9,10-DIHYDRO-2H-SPIRO[BICYCLO[3.1.0]HEXANE-2,3-IMIDAZO[5,1-A][2,6]NAPHTHYRIDINE]-1,5,7(8H)-TRIONE'>4RT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ztf\|4ztf]]</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=4ztj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ztj OCA], [http://pdbe.org/4ztj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ztj RCSB], [http://www.ebi.ac.uk/pdbsum/4ztj PDBsum]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/POL_FOAMV POL_FOAMV]] The aspartyl protease activity mediates proteolytic cleavages of Gag and Pol polyproteins. The reverse transcriptase (RT) activity converts the viral RNA genome into dsDNA in the cytoplasm, shortly after virus entry into the cell (early reverse transcription) or after proviral DNA transcription (late reverse transcription). RT consists of 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-Lys1,2 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 a polypurine tract (PPT) 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 PPT that has not been removed by RNase H as primer. PPT 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). 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 at least the viral genome, matrix protein, and integrase. This complex is called the pre-integration complex (PIC). The integrase protein removes 2 nucleotides from the 3' end of the viral DNA right (U5) end, leaving the left (U3) intact. In the second step, the PIC enters cell nucleus. This process is mediated through the integrase and allows the virus to infect both dividing (nuclear membrane disassembled) and G1/S-arrested cells (active translocation), but with no viral gene expression in the latter. 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. It is however not clear how integration then proceeds to resolve the asymmetrical cleavage of viral DNA (By similarity).
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The search for new molecular constructs that resemble the critical 2-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetics to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules.

-	~~The entry 4ztj is ON HOLD until Paper Publication~~	+	Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors.,Raheem I, Walji A, Klein D, Sanders JM, Powell D, Abeywickrema P, Barbe G, Bennet A, Clas SD, Dubost D, Embrey M, Grobler J, Hafey M, Hartingh TJ, Hazuda DJ, Miller MD, Moore KP, Pajkovic N, Patel S, Rada V, Rearden P, Schreier JD, Sisko J, Steele TG, Truchon JF, Wai J, Xu M, Coleman PJ J Med Chem. 2015 Sep 23. PMID:26397965<ref>PMID:26397965</ref>

-	~~Authors: Klein~~, D.~~J., Patel,~~ S.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description: Crystal Structure of the Prototype Foamy Virus Intasome with a 2~~-~~Pyridinone Aminal Inhibitor~~	+	<div class="pdbe-citations 4ztj" style="background-color:#fffaf0;"></div>
-	~~[[Category: Unreleased Structures]]~~	+	== References ==
-	[[Category: Klein, D.J]]	+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Klein, D J]]
	[[Category: Patel, S]]		[[Category: Patel, S]]
		+	[[Category: Dna integration]]
		+	[[Category: Recombination-inhibitor-dna complex]]
		+	[[Category: Transferase-dna complex]]
		+	[[Category: Transferase-dna-inhibitor complex]]
		+	[[Category: Viral protein]]

OCA at 12:18, 10 June 2015

OCA — Wed, 10 Jun 2015 12:18:26 GMT

←Older revision		Revision as of 12:18, 10 June 2015
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4ztj is ON HOLD	+	The entry 4ztj is ON HOLD until Paper Publication

	Authors: Klein, D.J., Patel, S.		Authors: Klein, D.J., Patel, S.

OCA: Protected "4ztj" [edit=sysop:move=sysop]

OCA — Wed, 20 May 2015 11:09:47 GMT

Protected "4ztj" [edit=sysop:move=sysop]

←Older revision

Revision as of 11:09, 20 May 2015

OCA: New page: '''Unreleased structure''' The entry 4ztj is ON HOLD Authors: Klein, D.J., Patel, S. Description: Crystal Structure of the Prototype Foamy Virus Intasome with a 2-Pyridinone Aminal Inh...

OCA — Wed, 20 May 2015 11:09:46 GMT

New page: '''Unreleased structure''' The entry 4ztj is ON HOLD Authors: Klein, D.J., Patel, S. Description: Crystal Structure of the Prototype Foamy Virus Intasome with a 2-Pyridinone Aminal Inh...

New page

'''Unreleased structure'''

The entry 4ztj is ON HOLD

Authors: Klein, D.J., Patel, S.

Description: Crystal Structure of the Prototype Foamy Virus Intasome with a 2-Pyridinone Aminal Inhibitor
[[Category: Unreleased Structures]]
[[Category: Klein, D.J]]
[[Category: Patel, S]]