View source for 6opu


==HIV-1 Protease NL4-3 K45I, M46I, V82F, I84V Mutant in complex with darunavir==
<StructureSection load='6opu' size='340' side='right'caption='[[6opu]], [[Resolution|resolution]] 1.94&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6opu]] 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=6OPU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OPU FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.94&#8491;</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6opu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6opu OCA], [https://pdbe.org/6opu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6opu RCSB], [https://www.ebi.ac.uk/pdbsum/6opu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6opu ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q7ZCI0_9HIV1 Q7ZCI0_9HIV1] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Drug resistance continues to be a growing global problem. The efficacy of small molecule inhibitors is threatened by pools of genetic diversity in all systems, including antibacterials, antifungals, cancer therapeutics, and antivirals. Resistant variants often include combinations of active site mutations and distal "secondary" mutations, which are thought to compensate for losses in enzymatic activity. HIV-1 protease is the ideal model system to investigate these combinations and underlying molecular mechanisms of resistance. Darunavir (DRV) binds wild-type (WT) HIV-1 protease with a potency of &lt;5 pM, but we have identified a protease variant that loses potency to DRV 150000-fold, with 11 mutations in and outside the active site. To elucidate the roles of these mutations in DRV resistance, we used a multidisciplinary approach, combining enzymatic assays, crystallography, and molecular dynamics simulations. Analysis of protease variants with 1, 2, 4, 8, 9, 10, and 11 mutations showed that the primary active site mutations caused approximately 50-fold loss in potency (2 mutations), while distal mutations outside the active site further decreased DRV potency from 13 nM (8 mutations) to 0.76 muM (11 mutations). Crystal structures and simulations revealed that distal mutations induce subtle changes that are dynamically propagated through the protease. Our results reveal that changes remote from the active site directly and dramatically impact the potency of the inhibitor. Moreover, we find interdependent effects of mutations in conferring high levels of resistance. These mechanisms of resistance are likely applicable to many other quickly evolving drug targets, and the insights may have implications for the design of more robust inhibitors.

Picomolar to Micromolar: Elucidating the Role of Distal Mutations in HIV-1 Protease in Conferring Drug Resistance.,Henes M, Lockbaum GJ, Kosovrasti K, Leidner F, Nachum GS, Nalivaika EA, Lee SK, Spielvogel E, Zhou S, Swanstrom R, Bolon DNA, Kurt Yilmaz N, Schiffer CA ACS Chem Biol. 2019 Nov 15;14(11):2441-2452. doi: 10.1021/acschembio.9b00370., Epub 2019 Aug 13. PMID:31361460<ref>PMID:31361460</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6opu" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human immunodeficiency virus 1]]
[[Category: Large Structures]]
[[Category: Bolon DNA]]
[[Category: Henes M]]
[[Category: Kosovrasti K]]
[[Category: KurtYilmaz N]]
[[Category: Leidner F]]
[[Category: Lockbaum GJ]]
[[Category: Nachum GS]]
[[Category: Nalivaika EA]]
[[Category: Schiffer CA]]