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[[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]] 2.49&Aring;' 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.


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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>
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{{STRUCTURE_3s3m|  PDB=3s3m  |  SCENE=  }}


===Crystal structure of the Prototype Foamy Virus (PFV) intasome in complex with magnesium and Dolutegravir (S/GSK1349572)===
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
 
</div>
 
== References ==
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{{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.]]

Revision as of 08:28, 5 June 2014

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)

Structural highlights

3s3m is a 4 chain structure with sequence from Human spumaretrovirus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, , , , , ,
Related:3l2u, 3oy9, 3oya, 3oyb, 3oyk, 3oyl, 3oym, 3oyn, 3s3n, 3s3o
Gene:pol (Human spumaretrovirus)
Resources:FirstGlance, OCA, RCSB, PDBsum

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[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Hare S, Smith SJ, Metifiot M, Jaxa-Chamiec A, Pommier Y, Hughes SH, Cherepanov P. Structural and Functional Analyses of the Second-generation Integrase Strand Transfer Inhibitor Dolutegravir (S/GSK1349572). Mol Pharmacol. 2011 Jun 30. PMID:21719464 doi:10.1124/mol.111.073189

3s3m, resolution 2.49Å

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