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| ==Darunavir in Complex with a Human Immunodeficiency Virus Type 1 Protease Variant== | | ==Darunavir in Complex with a Human Immunodeficiency Virus Type 1 Protease Variant== |
| <StructureSection load='3so9' size='340' side='right' caption='[[3so9]], [[Resolution|resolution]] 2.87Å' scene=''> | | <StructureSection load='3so9' size='340' side='right'caption='[[3so9]], [[Resolution|resolution]] 2.87Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[3so9]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SO9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SO9 FirstGlance]. <br> | | <table><tr><td colspan='2'>[[3so9]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SO9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SO9 FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=017:(3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YL(1S,2R)-3-[[(4-AMINOPHENYL)SULFONYL](ISOBUTYL)AMINO]-1-BENZYL-2-HYDROXYPROPYLCARBAMATE'>017</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]] 2.87Å</td></tr> |
| <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1tw7|1tw7]], [[1rpi|1rpi]], [[3oq7|3oq7]], [[3oqa|3oqa]], [[3oqd|3oqd]], [[3spk|3spk]]</td></tr>
| | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=017:(3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YL(1S,2R)-3-[[(4-AMINOPHENYL)SULFONYL](ISOBUTYL)AMINO]-1-BENZYL-2-HYDROXYPROPYLCARBAMATE'>017</scene></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=11676 Human immunodeficiency virus 1])</td></tr> | | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3so9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3so9 OCA], [https://pdbe.org/3so9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3so9 RCSB], [https://www.ebi.ac.uk/pdbsum/3so9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3so9 ProSAT]</span></td></tr> |
| <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/HIV-1_retropepsin HIV-1 retropepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.16 3.4.23.16] </span></td></tr>
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| <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=3so9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3so9 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3so9 RCSB], [http://www.ebi.ac.uk/pdbsum/3so9 PDBsum]</span></td></tr> | |
| </table> | | </table> |
| <div style="background-color:#fffaf0;">
| | == Function == |
| == Publication Abstract from PubMed == | | [https://www.uniprot.org/uniprot/Q000H7_9HIV1 Q000H7_9HIV1] |
| Darunavir and tipranavir are two inhibitors that are active against multi-drug resistant (MDR) HIV-1 protease variants. In this study, the invitro inhibitory efficacy was tested against a MDR HIV-1 protease variant, MDR 769 82T, containing the drug resistance mutations of 46L/54V/82T/84V/90M. Crystallographic and enzymatic studies were performed to examine the mechanism of resistance and the relative maintenance of potency. The key findings are as follows: (i) The MDR protease exhibits decreased susceptibility to all nine HIV-1 protease inhibitors approved by the US Food and Drug Administration (FDA), among which darunavir and tipranavir are the most potent; (ii) the threonine 82 mutation on the protease greatly enhances drug resistance by altering the hydrophobicity of the binding pocket; (iii) darunavir or tipranavir binding facilitates closure of the wide-open flaps of the MDR protease; and (iv) the remaining potency of tipranavir may be preserved by stabilizing the flaps in the inhibitor-protease complex while darunavir maintains its potency by preserving protein main chain hydrogen bonds with the flexible P2 group. These results could provide new insights into drug design strategies to overcome multi-drug resistance of HIV-1 protease variants.
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| The higher barrier of darunavir and tipranavir resistance for HIV-1 protease.,Wang Y, Liu Z, Brunzelle JS, Kovari IA, Dewdney TG, Reiter SJ, Kovari LC Biochem Biophys Res Commun. 2011 Sep 9;412(4):737-42. Epub 2011 Aug 17. PMID:21871444<ref>PMID:21871444</ref>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| ==See Also== | | ==See Also== |
| *[[Virus protease|Virus protease]] | | *[[Immunodeficiency virus protease 3D structures|Immunodeficiency virus protease 3D structures]] |
| == References ==
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| <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: HIV-1 retropepsin]]
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| [[Category: Human immunodeficiency virus 1]] | | [[Category: Human immunodeficiency virus 1]] |
| [[Category: Brunzelle, S J]] | | [[Category: Large Structures]] |
| [[Category: Kovari, I A]] | | [[Category: Brunzelle SJ]] |
| [[Category: Kovari, L C]] | | [[Category: Kovari IA]] |
| [[Category: Liu, Z]] | | [[Category: Kovari LC]] |
| [[Category: Wang, Y]] | | [[Category: Liu Z]] |
| [[Category: Darunavir]] | | [[Category: Wang Y]] |
| [[Category: Hiv-1 protease]]
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| [[Category: Hydorlase-hydorlase inhibitor complex]]
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| [[Category: Multi-drug resistance]]
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| [[Category: Protease inhibitor]]
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