3s3m - Revision history

OCA at 12:45, 14 March 2024

2024-03-14T12:45:18Z

←Older revision		Revision as of 12:45, 14 March 2024
Line 3:		Line 3:
	<StructureSection load='3s3m' size='340' side='right'caption='[[3s3m]], [[Resolution\|resolution]] 2.49Å' scene=''>		<StructureSection load='3s3m' size='340' side='right'caption='[[3s3m]], [[Resolution\|resolution]] 2.49Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3s3m]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Foamv Foamv~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3S3M FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3s3m]] 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=3S3M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3S3M FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DLU:(4R,12AS)-N-(2,4-DIFLUOROBENZYL)-7-HYDROXY-4-METHYL-6,8-DIOXO-3,4,6,8,12,12A-HEXAHYDRO-2H-PYRIDO[1,2 4,5]PYRAZINO[2,1-B][1,3]OXAZINE-9-CARBOXAMIDE'>DLU</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEZ:HEXANE-1,6-DIOL'>HEZ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NH4:AMMONIUM+ION'>NH4</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]] 2.49Å</td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3l2u\|3l2u]], [[3oy9\|3oy9]], [[3oya\|3oya]], [[3oyb\|3oyb]], [[3oyk\|3oyk]], [[3oyl\|3oyl]], [[3oym\|3oym]], [[3oyn\|3oyn]], [[3s3n\|3s3n]], [[3s3o\|3s3o]]</div></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DLU:(4R,12AS)-N-(2,4-DIFLUOROBENZYL)-7-HYDROXY-4-METHYL-6,8-DIOXO-3,4,6,8,12,12A-HEXAHYDRO-2H-PYRIDO[1,2 4,5]PYRAZINO[2,1-B][1,3]OXAZINE-9-CARBOXAMIDE'>DLU</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEZ:HEXANE-1,6-DIOL'>HEZ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NH4:AMMONIUM+ION'>NH4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">pol ([https://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'>[https://proteopedia.org/fgij/fg.htm?mol=3s3m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s3m OCA], [https://pdbe.org/3s3m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3s3m RCSB], [https://www.ebi.ac.uk/pdbsum/3s3m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3s3m 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=3s3m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s3m OCA], [https://pdbe.org/3s3m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3s3m RCSB], [https://www.ebi.ac.uk/pdbsum/3s3m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3s3m 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 ==~~	+
-	Raltegravir (RAL) and related HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) efficiently block viral replication in vitro and suppress viremia in patients. These small molecules bind to the IN active site causing it to disengage from the deoxyadenosine at the 3' end of viral DNA. The emergence of viral strains that are highly resistant to RAL underscores the pressing need to develop INSTIs with improved resistance profiles. Herein, we show that the candidate second-generation drug Dolutegravir (DTG, S/GSK1349572) effectively inhibits a panel of HIV 1 IN variants resistant to first-generation INSTIs. To elucidate the structural basis for the increased potency of DTG against RAL resistant INs, we determined crystal structures of wild type and mutant prototype foamy virus intasomes bound to this compound. The overall IN binding mode of DTG is strikingly similar to that of the tricyclic hydroxypyrrole MK2048. Both second-generation INSTIs occupy almost the same physical space within the IN active site and make contacts with the beta4-alpha2 loop of the catalytic core domain. The extended linker region connecting the metal chelating core and the halobenzyl group of DTG allows it to enter farther into the pocket vacated by the displaced viral DNA base and to make more intimate contacts with viral DNA, compared to those made by RAL and other INSTIs. In addition, our structures suggest that DTG has the ability to subtly readjust its position and conformation in response to structural changes in the active sites of RAL-resistant INs.	+

-	Structural and Functional Analyses of the Second-generation Integrase Strand Transfer Inhibitor Dolutegravir (S/GSK1349572).,Hare S, Smith SJ, Metifiot M, Jaxa-Chamiec A, Pommier Y, Hughes SH, Cherepanov P Mol Pharmacol. 2011 Jun 30. PMID:21719464<ref>PMID:21719464</ref>	+	==See Also==
-		+	*[[Retroviral integrase 3D structures\|Retroviral integrase 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 3s3m" style="background-color:#fffaf0;"></div>~~	+
-	== ~~References~~ ==	+
-	~~<references/>~~	+
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Foamv~~]]	+	[[Category: Human spumaretrovirus]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Cherepanov, P]]	+	[[Category: Cherepanov P]]
-	[[Category: Hare, S]]	+	[[Category: Hare S]]
-	~~[[Category: Dna integration]]~~	+
-	~~[[Category: Dna-binding]]~~	+
-	~~[[Category: Endonuclease]]~~	+
-	~~[[Category: Hhcc motif]]~~	+
-	~~[[Category: Inhibitor]]~~	+
-	~~[[Category: Metal-binding]]~~	+
-	~~[[Category: Multifunctional enzyme]]~~	+
-	~~[[Category: Nuclease]]~~	+
-	~~[[Category: Nucleotidyltransferase]]~~	+
-	~~[[Category: Nucleus]]~~	+
-	~~[[Category: Protein-dna complex]]~~	+
-	~~[[Category: Recombination]]~~	+
-	~~[[Category: Recombination-inhibitor-dna complex]]~~	+
-	~~[[Category: Tetramer]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Viral nucleoprotein]]~~	+
-	~~[[Category: Viral protein]]~~	+
-	~~[[Category: Virion]]~~	+
-	~~[[Category: Zinc binding~~]]	+

OCA at 10:36, 22 June 2022

2022-06-22T10:36:48Z

←Older revision		Revision as of 10:36, 22 June 2022
Line 1:		Line 1:

	==Crystal structure of the Prototype Foamy Virus (PFV) intasome in complex with magnesium and Dolutegravir (S/GSK1349572)==		==Crystal structure of the Prototype Foamy Virus (PFV) intasome in complex with magnesium and Dolutegravir (S/GSK1349572)==
-	<StructureSection load='3s3m' size='340' side='right' caption='[[3s3m]], [[Resolution\|resolution]] 2.49Å' scene=''>	+	<StructureSection load='3s3m' size='340' side='right'caption='[[3s3m]], [[Resolution\|resolution]] 2.49Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3s3m]] is a 4 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/Foamv Foamv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3M OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3S3M FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3s3m]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Foamv Foamv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3S3M FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DLU:(4R,12AS)-N-(2,4-DIFLUOROBENZYL)-7-HYDROXY-4-METHYL-6,8-DIOXO-3,4,6,8,12,12A-HEXAHYDRO-2H-PYRIDO[1,2 4,5]PYRAZINO[2,1-B][1,3]OXAZINE-9-CARBOXAMIDE'>DLU</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEZ:HEXANE-1,6-DIOL'>HEZ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NH4:AMMONIUM+ION'>NH4</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=DLU:(4R,12AS)-N-(2,4-DIFLUOROBENZYL)-7-HYDROXY-4-METHYL-6,8-DIOXO-3,4,6,8,12,12A-HEXAHYDRO-2H-PYRIDO[1,2 4,5]PYRAZINO[2,1-B][1,3]OXAZINE-9-CARBOXAMIDE'>DLU</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEZ:HEXANE-1,6-DIOL'>HEZ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NH4:AMMONIUM+ION'>NH4</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">[[3l2u\|3l2u]], [[3oy9\|3oy9]], [[3oya\|3oya]], [[3oyb\|3oyb]], [[3oyk\|3oyk]], [[3oyl\|3oyl]], [[3oym\|3oym]], [[3oyn\|3oyn]], [[3s3n\|3s3n]], [[3s3o\|3s3o]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3l2u\|3l2u]], [[3oy9\|3oy9]], [[3oya\|3oya]], [[3oyb\|3oyb]], [[3oyk\|3oyk]], [[3oyl\|3oyl]], [[3oym\|3oym]], [[3oyn\|3oyn]], [[3s3n\|3s3n]], [[3s3o\|3s3o]]</div></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='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">pol ([https://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=3s3m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s3m OCA], [~~http~~://pdbe.org/3s3m PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3s3m RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3s3m PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3s3m 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=3s3m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s3m OCA], [https://pdbe.org/3s3m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3s3m RCSB], [https://www.ebi.ac.uk/pdbsum/3s3m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3s3m 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 25:		Line 25:
	</StructureSection>		</StructureSection>
	[[Category: Foamv]]		[[Category: Foamv]]
		+	[[Category: Large Structures]]
	[[Category: Cherepanov, P]]		[[Category: Cherepanov, P]]
	[[Category: Hare, S]]		[[Category: Hare, S]]

OCA at 16:45, 5 August 2016

2016-08-05T16:45:07Z

←Older revision		Revision as of 16:45, 5 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of the Prototype Foamy Virus (PFV) intasome in complex with magnesium and Dolutegravir (S/GSK1349572)==		==Crystal structure of the Prototype Foamy Virus (PFV) intasome in complex with magnesium and Dolutegravir (S/GSK1349572)==
	<StructureSection load='3s3m' size='340' side='right' caption='[[3s3m]], [[Resolution\|resolution]] 2.49Å' scene=''>		<StructureSection load='3s3m' size='340' side='right' caption='[[3s3m]], [[Resolution\|resolution]] 2.49Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3s3m]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Human_spumaretrovirus Human spumaretrovirus~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3S3M FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3s3m]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Foamv Foamv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3S3M FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DLU:(4R,12AS)-N-(2,4-DIFLUOROBENZYL)-7-HYDROXY-4-METHYL-6,8-DIOXO-3,4,6,8,12,12A-HEXAHYDRO-2H-PYRIDO[1,2 4,5]PYRAZINO[2,1-B][1,3]OXAZINE-9-CARBOXAMIDE'>DLU</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEZ:HEXANE-1,6-DIOL'>HEZ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NH4:AMMONIUM+ION'>NH4</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=DLU:(4R,12AS)-N-(2,4-DIFLUOROBENZYL)-7-HYDROXY-4-METHYL-6,8-DIOXO-3,4,6,8,12,12A-HEXAHYDRO-2H-PYRIDO[1,2 4,5]PYRAZINO[2,1-B][1,3]OXAZINE-9-CARBOXAMIDE'>DLU</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEZ:HEXANE-1,6-DIOL'>HEZ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NH4:AMMONIUM+ION'>NH4</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">[[3l2u\|3l2u]], [[3oy9\|3oy9]], [[3oya\|3oya]], [[3oyb\|3oyb]], [[3oyk\|3oyk]], [[3oyl\|3oyl]], [[3oym\|3oym]], [[3oyn\|3oyn]], [[3s3n\|3s3n]], [[3s3o\|3s3o]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3l2u\|3l2u]], [[3oy9\|3oy9]], [[3oya\|3oya]], [[3oyb\|3oyb]], [[3oyk\|3oyk]], [[3oyl\|3oyl]], [[3oym\|3oym]], [[3oyn\|3oyn]], [[3s3n\|3s3n]], [[3s3o\|3s3o]]</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 ~~Human spumaretrovirus~~])</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=3s3m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s3m OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3s3m RCSB], [http://www.ebi.ac.uk/pdbsum/3s3m 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=3s3m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s3m OCA], [http://pdbe.org/3s3m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3s3m RCSB], [http://www.ebi.ac.uk/pdbsum/3s3m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3s3m 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 3s3m" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human spumaretrovirus~~]]	+	[[Category: Foamv]]
	[[Category: Cherepanov, P]]		[[Category: Cherepanov, P]]
	[[Category: Hare, S]]		[[Category: Hare, S]]

OCA at 04:07, 25 December 2014

2014-12-25T04:07:12Z

←Older revision		Revision as of 04:07, 25 December 2014
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[3s3m]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human_spumaretrovirus Human spumaretrovirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3S3M FirstGlance]. <br>		<table><tr><td colspan='2'>[[3s3m]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human_spumaretrovirus Human spumaretrovirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3S3M FirstGlance]. <br>
-	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DLU:(4R,12AS)-N-(2,4-DIFLUOROBENZYL)-7-HYDROXY-4-METHYL-6,8-DIOXO-3,4,6,8,12,12A-HEXAHYDRO-2H-PYRIDO[1,2 4,5]PYRAZINO[2,1-B][1,3]OXAZINE-9-CARBOXAMIDE'>DLU</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEZ:HEXANE-1,6-DIOL'>HEZ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NH4:AMMONIUM+ION'>NH4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene><br>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DLU:(4R,12AS)-N-(2,4-DIFLUOROBENZYL)-7-HYDROXY-4-METHYL-6,8-DIOXO-3,4,6,8,12,12A-HEXAHYDRO-2H-PYRIDO[1,2 4,5]PYRAZINO[2,1-B][1,3]OXAZINE-9-CARBOXAMIDE'>DLU</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEZ:HEXANE-1,6-DIOL'>HEZ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NH4:AMMONIUM+ION'>NH4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3l2u\|3l2u]], [[3oy9\|3oy9]], [[3oya\|3oya]], [[3oyb\|3oyb]], [[3oyk\|3oyk]], [[3oyl\|3oyl]], [[3oym\|3oym]], [[3oyn\|3oyn]], [[3s3n\|3s3n]], [[3s3o\|3s3o]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3l2u\|3l2u]], [[3oy9\|3oy9]], [[3oya\|3oya]], [[3oyb\|3oyb]], [[3oyk\|3oyk]], [[3oyl\|3oyl]], [[3oym\|3oym]], [[3oyn\|3oyn]], [[3s3n\|3s3n]], [[3s3o\|3s3o]]</td></tr>
-	<tr><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 Human spumaretrovirus])</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 Human spumaretrovirus])</td></tr>
-	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3s3m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s3m OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3s3m RCSB], [http://www.ebi.ac.uk/pdbsum/3s3m 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=3s3m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s3m OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3s3m RCSB], [http://www.ebi.ac.uk/pdbsum/3s3m PDBsum]</span></td></tr>
-	<table>	+	</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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 14:		Line 16:
	Structural and Functional Analyses of the Second-generation Integrase Strand Transfer Inhibitor Dolutegravir (S/GSK1349572).,Hare S, Smith SJ, Metifiot M, Jaxa-Chamiec A, Pommier Y, Hughes SH, Cherepanov P Mol Pharmacol. 2011 Jun 30. PMID:21719464<ref>PMID:21719464</ref>		Structural and Functional Analyses of the Second-generation Integrase Strand Transfer Inhibitor Dolutegravir (S/GSK1349572).,Hare S, Smith SJ, Metifiot M, Jaxa-Chamiec A, Pommier Y, Hughes SH, Cherepanov P Mol Pharmacol. 2011 Jun 30. PMID:21719464<ref>PMID:21719464</ref>

-	From ~~MEDLINEÂ®~~/~~PubMedÂ®~~, 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>
	== References ==		== References ==
Line 21:		Line 23:
	</StructureSection>		</StructureSection>
	[[Category: Human spumaretrovirus]]		[[Category: Human spumaretrovirus]]
-	[[Category: Cherepanov, P.]]	+	[[Category: Cherepanov, P]]
-	[[Category: Hare, S.]]	+	[[Category: Hare, S]]
	[[Category: Dna integration]]		[[Category: Dna integration]]
	[[Category: Dna-binding]]		[[Category: Dna-binding]]

OCA at 05:28, 5 June 2014

2014-06-05T05:28:49Z

←Older revision		Revision as of 05:28, 5 June 2014
Line 1:		Line 1:
-	[[~~Image:~~3s3m.~~png~~\|~~left~~\|~~200px~~]]	+	==Crystal structure of the Prototype Foamy Virus (PFV) intasome in complex with magnesium and Dolutegravir (S/GSK1349572)==
		+	<StructureSection load='3s3m' size='340' side='right' caption='[[3s3m]], [[Resolution\|resolution]] 2.49Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[3s3m]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human_spumaretrovirus Human spumaretrovirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3S3M FirstGlance]. <br>
		+	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DLU:(4R,12AS)-N-(2,4-DIFLUOROBENZYL)-7-HYDROXY-4-METHYL-6,8-DIOXO-3,4,6,8,12,12A-HEXAHYDRO-2H-PYRIDO[1,2 4,5]PYRAZINO[2,1-B][1,3]OXAZINE-9-CARBOXAMIDE'>DLU</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEZ:HEXANE-1,6-DIOL'>HEZ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NH4:AMMONIUM+ION'>NH4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene><br>
		+	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3l2u\|3l2u]], [[3oy9\|3oy9]], [[3oya\|3oya]], [[3oyb\|3oyb]], [[3oyk\|3oyk]], [[3oyl\|3oyl]], [[3oym\|3oym]], [[3oyn\|3oyn]], [[3s3n\|3s3n]], [[3s3o\|3s3o]]</td></tr>
		+	<tr><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 Human spumaretrovirus])</td></tr>
		+	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3s3m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s3m OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3s3m RCSB], [http://www.ebi.ac.uk/pdbsum/3s3m PDBsum]</span></td></tr>
		+	<table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Raltegravir (RAL) and related HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) efficiently block viral replication in vitro and suppress viremia in patients. These small molecules bind to the IN active site causing it to disengage from the deoxyadenosine at the 3' end of viral DNA. The emergence of viral strains that are highly resistant to RAL underscores the pressing need to develop INSTIs with improved resistance profiles. Herein, we show that the candidate second-generation drug Dolutegravir (DTG, S/GSK1349572) effectively inhibits a panel of HIV 1 IN variants resistant to first-generation INSTIs. To elucidate the structural basis for the increased potency of DTG against RAL resistant INs, we determined crystal structures of wild type and mutant prototype foamy virus intasomes bound to this compound. The overall IN binding mode of DTG is strikingly similar to that of the tricyclic hydroxypyrrole MK2048. Both second-generation INSTIs occupy almost the same physical space within the IN active site and make contacts with the beta4-alpha2 loop of the catalytic core domain. The extended linker region connecting the metal chelating core and the halobenzyl group of DTG allows it to enter farther into the pocket vacated by the displaced viral DNA base and to make more intimate contacts with viral DNA, compared to those made by RAL and other INSTIs. In addition, our structures suggest that DTG has the ability to subtly readjust its position and conformation in response to structural changes in the active sites of RAL-resistant INs.

-	<!--	+	Structural and Functional Analyses of the Second-generation Integrase Strand Transfer Inhibitor Dolutegravir (S/GSK1349572).,Hare S, Smith SJ, Metifiot M, Jaxa-Chamiec A, Pommier Y, Hughes SH, Cherepanov P Mol Pharmacol. 2011 Jun 30. PMID:21719464<ref>PMID:21719464</ref>
-	~~The line below this paragraph~~, ~~containing "STRUCTURE_3s3m"~~, ~~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_3s3m\| PDB=3s3m \| SCENE= }}~~	+

-	~~===Crystal structure of the Prototype Foamy Virus (PFV) intasome in complex with magnesium and Dolutegravir (S~~/~~GSK1349572)===~~	+	From MEDLINEÂ®/PubMedÂ®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-		+	== References ==
-	~~<!--~~	+	<references/>
-	~~The line below this paragraph~~, ~~{{ABSTRACT_PUBMED_21719464}}, adds~~ the ~~Publication Abstract to the page~~	+	__TOC__
-	~~(as it appears on PubMed at http://www~~.~~pubmed~~.~~gov), where 21719464 is the PubMed ID number~~.	+	</StructureSection>
-	-->	+
-	~~{{ABSTRACT_PUBMED_21719464}}~~	+
-		+
-	~~==About this Structure==~~	+
-	~~[[3s3m]] is a 4 chain structure with sequence from [http:~~/~~/en.wikipedia.org/wiki/Human_spumaretrovirus Human spumaretrovirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3M OCA].~~	+
-		+
-	==~~Reference~~==	+
-	<~~ref group="xtra">PMID:021719464<~~/~~ref~~><~~references group="xtra"~~/>	+
	[[Category: Human spumaretrovirus]]		[[Category: Human spumaretrovirus]]
	[[Category: Cherepanov, P.]]		[[Category: Cherepanov, P.]]

OCA at 05:48, 5 October 2011

2011-10-05T05:48:19Z

←Older revision		Revision as of 05:48, 5 October 2011
Line 1:		Line 1:
-	[[Image:3s3m.~~jpg~~\|left\|200px]]	+	[[Image:3s3m.png\|left\|200px]]

	<!--		<!--

OCA at 07:35, 13 July 2011

2011-07-13T07:35:13Z

←Older revision		Revision as of 07:35, 13 July 2011
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	[[Image:3s3m.jpg\|left\|200px]]

-	The ~~entry 3s3m~~ is ~~ON HOLD~~ ~~until Paper Publication~~	+	<!--
		+	The line below this paragraph, containing "STRUCTURE_3s3m", 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_3s3m\| PDB=3s3m \| SCENE= }}

-	~~Authors: Hare,~~ S~~., Cherepanov, P.~~	+	===Crystal structure of the Prototype Foamy Virus (PFV) intasome in complex with magnesium and Dolutegravir (S/GSK1349572)===

-	~~Description: Crystal structure of~~ the ~~Prototype Foamy Virus~~ (~~PFV~~) ~~intasome in complex~~ with ~~magnesium and Dolutegravir (S~~/~~GSK1349572)~~	+
		+	<!--
		+	The line below this paragraph, {{ABSTRACT_PUBMED_21719464}}, adds the Publication Abstract to the page
		+	(as it appears on PubMed at http://www.pubmed.gov), where 21719464 is the PubMed ID number.
		+	-->
		+	{{ABSTRACT_PUBMED_21719464}}
		+
		+	==About this Structure==
		+	[[3s3m]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human_spumaretrovirus Human spumaretrovirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3M OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:021719464</ref><references group="xtra"/>
		+	[[Category: Human spumaretrovirus]]
		+	[[Category: Cherepanov, P.]]
		+	[[Category: Hare, S.]]
		+	[[Category: Dna integration]]
		+	[[Category: Dna-binding]]
		+	[[Category: Endonuclease]]
		+	[[Category: Hhcc motif]]
		+	[[Category: Inhibitor]]
		+	[[Category: Metal-binding]]
		+	[[Category: Multifunctional enzyme]]
		+	[[Category: Nuclease]]
		+	[[Category: Nucleotidyltransferase]]
		+	[[Category: Nucleus]]
		+	[[Category: Protein-dna complex]]
		+	[[Category: Recombination]]
		+	[[Category: Recombination-inhibitor-dna complex]]
		+	[[Category: Tetramer]]
		+	[[Category: Transferase]]
		+	[[Category: Viral nucleoprotein]]
		+	[[Category: Viral protein]]
		+	[[Category: Virion]]
		+	[[Category: Zinc binding]]

OCA at 05:41, 29 June 2011

2011-06-29T05:41:16Z

←Older revision		Revision as of 05:41, 29 June 2011
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 3s3m is ON HOLD	+	The entry 3s3m is ON HOLD until Paper Publication

	Authors: Hare, S., Cherepanov, P.		Authors: Hare, S., Cherepanov, P.

	Description: Crystal structure of the Prototype Foamy Virus (PFV) intasome in complex with magnesium and Dolutegravir (S/GSK1349572)		Description: Crystal structure of the Prototype Foamy Virus (PFV) intasome in complex with magnesium and Dolutegravir (S/GSK1349572)

OCA: Protected "3s3m" [edit=sysop:move=sysop]

2011-05-25T05:15:50Z

Protected "3s3m" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:15, 25 May 2011

OCA: New page: '''Unreleased structure''' The entry 3s3m is ON HOLD Authors: Hare, S., Cherepanov, P. Description: Crystal structure of the Prototype Foamy Virus (PFV) intasome in complex with magnes...

2011-05-25T05:15:49Z

New page: '''Unreleased structure''' The entry 3s3m is ON HOLD Authors: Hare, S., Cherepanov, P. Description: Crystal structure of the Prototype Foamy Virus (PFV) intasome in complex with magnes...

New page

'''Unreleased structure'''

The entry 3s3m is ON HOLD

Authors: Hare, S., Cherepanov, P.

Description: Crystal structure of the Prototype Foamy Virus (PFV) intasome in complex with magnesium and Dolutegravir (S/GSK1349572)