3NU4

Crystal Structure of HIV-1 Protease Mutant V32I with Antiviral Drug Amprenavir


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.162 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters.

Shen, C.H.Wang, Y.F.Kovalevsky, A.Y.Harrison, R.W.Weber, I.T.

(2010) FEBS J 277: 3699-3714

  • DOI: https://doi.org/10.1111/j.1742-4658.2010.07771.x
  • Primary Citation of Related Structures:  
    3NU3, 3NU4, 3NU5, 3NU6, 3NU9, 3NUJ, 3NUO

  • PubMed Abstract: 

    The structural and kinetic effects of amprenavir (APV), a clinical HIV protease (PR) inhibitor, were analyzed with wild-type enzyme and mutants with single substitutions of V32I, I50V, I54V, I54M, I84V and L90M that are common in drug resistance. Crystal structures of the APV complexes at resolutions of 1.02-1.85 Å reveal the structural changes due to the mutations. Substitution of the larger side chains in PR(V32I) , PR(I54M) and PR(L90M) resulted in the formation of new hydrophobic contacts with flap residues, residues 79 and 80, and Asp25, respectively. Mutation to smaller side chains eliminated hydrophobic interactions in the PR(I50V) and PR(I54V) structures. The PR(I84V)-APV complex had lost hydrophobic contacts with APV, the PR(V32I)-APV complex showed increased hydrophobic contacts within the hydrophobic cluster and the PR(I50V) complex had weaker polar and hydrophobic interactions with APV. The observed structural changes in PR(I84V)-APV, PR(V32I)-APV and PR(I50V)-APV were related to their reduced inhibition by APV of six-, 10- and 30-fold, respectively, relative to wild-type PR. The APV complexes were compared with the corresponding saquinavir complexes. The PR dimers had distinct rearrangements of the flaps and 80's loops that adapt to the different P1' groups of the inhibitors, while maintaining contacts within the hydrophobic cluster. These small changes in the loops and weak internal interactions produce the different patterns of resistant mutations for the two drugs.


  • Organizational Affiliation

    Department of Biology, Molecular Basis of Disease Program, Georgia State University, Atlanta, GA, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
protease
A, B
99Human immunodeficiency virus 1Mutation(s): 6 
Gene Names: gagpol
EC: 3.4.23.16
UniProt
Find proteins for P03366 (Human immunodeficiency virus type 1 group M subtype B (isolate BH10))
Explore P03366 
Go to UniProtKB:  P03366
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03366
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
478 PDBBind:  3NU4 Ki: 1.5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.162 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 57.769α = 90
b = 86.13β = 90
c = 46.284γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
AMoREphasing
SHELXL-97refinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-08-25
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description