6O5A

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.178 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Highly Drug-Resistant HIV-1 Protease Mutant PRS17 Shows Enhanced Binding to Substrate Analogues.

Agniswamy, J.Kneller, D.W.Brothers, R.Wang, Y.F.Harrison, R.W.Weber, I.T.

(2019) ACS Omega 4: 8707-8719

  • DOI: https://doi.org/10.1021/acsomega.9b00683
  • Primary Citation of Related Structures:  
    6O48, 6O54, 6O57, 6O5A, 6O5X

  • PubMed Abstract: 

    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 β-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.


  • Organizational Affiliation

    Department of Biology, Georgia State University, P.O. Box 4010, Atlanta, Georgia 30302, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HIV-1 protease
A, B
99Human immunodeficiency virus 1Mutation(s): 7 
Gene Names: pol
UniProt
Find proteins for I7BFC3 (Human immunodeficiency virus 1)
Explore I7BFC3 
Go to UniProtKB:  I7BFC3
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupI7BFC3
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
2NC
Query on 2NC

Download Ideal Coordinates CCD File 
C [auth A]N-{(2S)-2-[(N-acetyl-L-threonyl-L-isoleucyl)amino]hexyl}-L-norleucyl-L-glutaminyl-N~5~-[amino(iminio)methyl]-L-ornithinamide
C35 H68 N11 O8
MQPXOVRKKPPKFZ-QYKDHROSSA-O
GOL
Query on GOL

Download Ideal Coordinates CCD File 
D [auth B]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
2NC Binding MOAD:  6O5A Ki: 514 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.178 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 63.833α = 90
b = 63.833β = 90
c = 83.039γ = 120
Software Package:
Software NamePurpose
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
REFMACrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)United StatesGM062920

Revision History  (Full details and data files)

  • Version 1.0: 2019-06-19
    Type: Initial release
  • Version 1.1: 2019-07-17
    Changes: Data collection, Structure summary
  • Version 1.2: 2019-12-18
    Changes: Author supporting evidence
  • Version 1.3: 2023-10-11
    Changes: Data collection, Database references, Refinement description