5T8H

Joint X-ray/neutron structure of HIV-1 protease triple mutant (V32I,I47V,V82I) with amprenavir at pH 6.0


Experimental Data Snapshot

  • Method: NEUTRON DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.217 

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.191 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Room Temperature Neutron Crystallography of Drug Resistant HIV-1 Protease Uncovers Limitations of X-ray Structural Analysis at 100 K.

Gerlits, O.Keen, D.A.Blakeley, M.P.Louis, J.M.Weber, I.T.Kovalevsky, A.

(2017) J Med Chem 60: 2018-2025

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b01767
  • Primary Citation of Related Structures:  
    5T8H

  • PubMed Abstract: 

    HIV-1 protease inhibitors are crucial for treatment of HIV-1/AIDS, but their effectiveness is thwarted by rapid emergence of drug resistance. To better understand binding of clinical inhibitors to resistant HIV-1 protease, we used room-temperature joint X-ray/neutron (XN) crystallography to obtain an atomic-resolution structure of the protease triple mutant (V32I/I47V/V82I) in complex with amprenavir. The XN structure reveals a D + ion located midway between the inner Oδ1 oxygen atoms of the catalytic aspartic acid residues. Comparison of the current XN structure with our previous XN structure of the wild-type HIV-1 protease-amprenavir complex suggests that the three mutations do not significantly alter the drug-enzyme interactions. This is in contrast to the observations in previous 100 K X-ray structures of these complexes that indicated loss of interactions by the drug with the triple mutant protease. These findings, thus, uncover limitations of structural analysis of drug binding using X-ray structures obtained at 100 K.


  • Organizational Affiliation

    UT/ORNL Joint Institute of Biological Sciences, University of Tennessee , Knoxville, Tennessee 37996, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protease
A, B
99Human immunodeficiency virus 1Mutation(s): 8 
Gene Names: pol
UniProt
Find proteins for Q7SSI0 (Human immunodeficiency virus 1)
Explore Q7SSI0 
Go to UniProtKB:  Q7SSI0
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ7SSI0
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
478
Query on 478

Download Ideal Coordinates CCD File 
C [auth B]{3-[(4-AMINO-BENZENESULFONYL)-ISOBUTYL-AMINO]-1-BENZYL-2-HYDROXY-PROPYL}-CARBAMIC ACID TETRAHYDRO-FURAN-3-YL ESTER
C25 H35 N3 O6 S
YMARZQAQMVYCKC-OEMFJLHTSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
478 BindingDB:  5T8H Ki: min: 7.00e-3, max: 63 (nM) from 17 assay(s)
Kd: min: 0.4, max: 0.59 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: NEUTRON DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.217 
  • Space Group: P 21 21 2
  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.191 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.234α = 90
b = 87.359β = 90
c = 46.565γ = 90
Software Package:
Software NamePurpose
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
nCNSrefinement
LAUEGENdata reduction
LSCALEdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-03-01
    Type: Initial release
  • Version 1.1: 2017-03-22
    Changes: Database references
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references