View source for 6dh7


==Crystal structure of HIV-1 Protease NL4-3 I50V Mutant in complex with UMass1==
<StructureSection load='6dh7' size='340' side='right'caption='[[6dh7]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6dh7]] 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=6DH7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DH7 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]] 1.997&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K13:(3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YL+[(1S,2R)-3-{[(4-AMINOPHENYL)SULFONYL][(2S)-2-METHYLBUTYL]AMINO}-1-BENZYL-2-HYDROXYPROPYL]CARBAMATE'>K13</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6dh7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dh7 OCA], [https://pdbe.org/6dh7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dh7 RCSB], [https://www.ebi.ac.uk/pdbsum/6dh7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dh7 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q7ZCR0_9HIV1 Q7ZCR0_9HIV1] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
HIV-1 protease is one of the prime targets of agents used in antiretroviral therapy against HIV. However, under selective pressure of protease inhibitors, primary mutations at the active site weaken inhibitor binding to confer resistance. Darunavir (DRV) is the most potent HIV-1 protease inhibitor in clinic; resistance is limited, as DRV fits well within the substrate envelope. Nevertheless, resistance is observed due to hydrophobic changes at residues including I50, V82 and I84 that line the S1/S1' pocket within the active site. Through enzyme inhibition assays and a series of 12 crystal structures, we interrogated susceptibility of DRV and two potent analogs to primary S1' mutations. The analogs had modifications at the hydrophobic P1' moiety compared to DRV to better occupy the unexploited space in the S1' pocket where the primary mutations were located. Considerable losses of potency were observed against protease variants with I84V and I50V mutations for all three inhibitors. The crystal structures revealed an unexpected conformational change in the flap region of I50V protease bound to the analog with the largest P1' moiety, indicating interdependency between the S1' subsite and the flap region. Collective analysis of protease-inhibitor interactions in the crystal structures using principle component analysis was able to distinguish inhibitor identity and relative potency solely based on vdW contacts. Our results reveal the complexity of the interplay between inhibitor P1' moiety and S1' mutations, and validate principle component analyses as a useful tool for distinguishing resistance and inhibitor potency.

Structural Adaptation of Darunavir Analogs Against Primary Mutations in HIV-1 Protease.,Lockbaum GJ, Leidner F, Rusere LN, Henes M, Kosovrasti K, Nachum GS, Nalivaika EA, Ali A, Kurt Yilmaz N, Schiffer CA ACS Infect Dis. 2018 Dec 13. doi: 10.1021/acsinfecdis.8b00336. PMID:30543749<ref>PMID:30543749</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6dh7" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Human immunodeficiency virus 1]]
[[Category: Large Structures]]
[[Category: Lockbaum GJ]]
[[Category: Schiffer CA]]