View source for 6o54


==Crystal Structure of multi-drug resistant HIV-1 protease PR-S17 (D25N)==
<StructureSection load='6o54' size='340' side='right'caption='[[6o54]], [[Resolution|resolution]] 1.21&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6o54]] is a 1 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=6O54 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6O54 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]] 1.21&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=6o54 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o54 OCA], [https://pdbe.org/6o54 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6o54 RCSB], [https://www.ebi.ac.uk/pdbsum/6o54 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6o54 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/I7BFC3_9HIV1 I7BFC3_9HIV1] 
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== Publication Abstract from PubMed ==
We report the structural analysis of highly drug-resistant human immunodeficiency virus protease (PR) variant PR(S17), rationally selected by machine learning, in complex with substrate analogues. Crystal structures were solved of inhibitor-free inactive PR(S17)-D25N, wild-type PR/CA-p2 complex, and PR(S17) in complex with substrate analogues, CA-p2 and p2-NC. Peptide analogues p2-NC and CA-p2 exhibit inhibition constants of 514 and 22 nM, respectively, for PR(S17) or approximately 3-fold better than for PR. CA-p2 is a better inhibitor of PR(S17) than are clinical inhibitors (K i = 50-8390 nM) except for amprenavir (K i = 11 nM). G48V resistance mutation induces curled flap tips in PR(S17)-D25N structure. The inner P2-P2' residues of substrate analogues in PR(S17) complexes maintain similar conformations to those of wild-type complex, while significant conformational changes are observed in the peripheral residues P3, P4' of CA-p2 and P3, P4, and P3' of p2-NC. The loss of beta-branched side chain by V82S mutation initiates a shift in 80's loop and reshapes the S3/S3' subsite, which enhances substrate binding with new hydrogen bonds and van der Waals interactions that are absent in the wild-type structures. The steric hindrance caused by G48V mutation in the flap of PR(S17) contributes to altered binding interactions of P3 Arg, P4' norleucine of CA-p2, and P4 and P3' of p2-NC with the addition of new hydrogen bonds and van der Waals contacts. The enhanced interaction of PR(S17) with substrate analogues agrees with their relative inhibition, suggesting that this mutant improves substrate binding while decreasing affinity for clinical inhibitors.

Highly Drug-Resistant HIV-1 Protease Mutant PRS17 Shows Enhanced Binding to Substrate Analogues.,Agniswamy J, Kneller DW, Brothers R, Wang YF, Harrison RW, Weber IT ACS Omega. 2019 May 31;4(5):8707-8719. doi: 10.1021/acsomega.9b00683. Epub 2019, May 17. PMID:31172041<ref>PMID:31172041</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6o54" style="background-color:#fffaf0;"></div>

==See Also==
*[[Immunodeficiency virus protease 3D structures|Immunodeficiency virus protease 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human immunodeficiency virus 1]]
[[Category: Large Structures]]
[[Category: Agniswamy J]]
[[Category: Brothers R]]
[[Category: Wang Y-F]]
[[Category: Weber IT]]