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6o5a

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Crystal Structure of multi-drug resistant HIV-1 protease PR-S17 with a substrate analog p2-NC in P61

Structural highlights

6o5a is a 2 chain structure with sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.67Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

I7BFC3_9HIV1

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^[1]

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

References

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

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6o5a"

Categories: Human immunodeficiency virus 1 | Large Structures | Agniswamy J | Wang Y-F | Weber IT

@@ Line 3: / Line 3: @@
 <StructureSection load='6o5a' size='340' side='right'caption='[[6o5a]], [[Resolution|resolution]] 1.67&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6o5a]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O5A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O5A FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6o5a]] 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=6O5A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6O5A FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2NC:N-{(2S)-2-[(N-ACETYL-L-THREONYL-L-ISOLEUCYL)AMINO]HEXYL}-L-NORLEUCYL-L-GLUTAMINYL-N~5~-[AMINO(IMINIO)METHYL]-L-ORNITHINAMIDE'>2NC</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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]] 1.67&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6o57|6o57]], [[2aod|2aod]], [[6o48|6o48]], [[6o54|6o54]], [[5t2e|5t2e]], [[6o5x|6o5x]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2NC:N-{(2S)-2-[(N-ACETYL-L-THREONYL-L-ISOLEUCYL)AMINO]HEXYL}-L-NORLEUCYL-L-GLUTAMINYL-N~5~-[AMINO(IMINIO)METHYL]-L-ORNITHINAMIDE'>2NC</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
-<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=6o5a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o5a OCA], [http://pdbe.org/6o5a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o5a RCSB], [http://www.ebi.ac.uk/pdbsum/6o5a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o5a ProSAT]</span></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=6o5a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o5a OCA], [https://pdbe.org/6o5a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6o5a RCSB], [https://www.ebi.ac.uk/pdbsum/6o5a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6o5a ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/I7BFC3_9HIV1 I7BFC3_9HIV1]
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 17: / Line 19: @@
 </div>
 <div class="pdbe-citations 6o5a" 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: Agniswamy J]]
-[[Category: Wang, Y F]]
+[[Category: Wang Y-F]]
-[[Category: Weber, I T]]
+[[Category: Weber IT]]
-[[Category: Hiv protease]]
-[[Category: Hydrolase]]
-[[Category: Viral protein]]

6o5a

From Proteopedia

Current revision

Crystal Structure of multi-drug resistant HIV-1 protease PR-S17 with a substrate analog p2-NC in P61

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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