3OXW

Crystal Structure of HIV-1 I50V, A71V Protease in Complex with the Protease Inhibitor Darunavir


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.175 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structural and thermodynamic basis of amprenavir/darunavir and atazanavir resistance in HIV-1 protease with mutations at residue 50.

Mittal, S.Bandaranayake, R.M.King, N.M.Prabu-Jeyabalan, M.Nalam, M.N.Nalivaika, E.A.Yilmaz, N.K.Schiffer, C.A.

(2013) J Virol 87: 4176-4184

  • DOI: https://doi.org/10.1128/JVI.03486-12
  • Primary Citation of Related Structures:  
    3OXV, 3OXW, 3OXX

  • PubMed Abstract: 

    Drug resistance occurs through a series of subtle changes that maintain substrate recognition but no longer permit inhibitor binding. In HIV-1 protease, mutations at I50 are associated with such subtle changes that confer differential resistance to specific inhibitors. Residue I50 is located at the protease flap tips, closing the active site upon ligand binding. Under selective drug pressure, I50V/L substitutions emerge in patients, compromising drug susceptibility and leading to treatment failure. The I50V substitution is often associated with amprenavir (APV) and darunavir (DRV) resistance, while the I50L substitution is observed in patients failing atazanavir (ATV) therapy. To explain how APV, DRV, and ATV susceptibility are influenced by mutations at residue 50 in HIV-1 protease, structural and binding thermodynamics studies were carried out on I50V/L-substituted protease variants in the compensatory mutation A71V background. Reduced affinity to both I50V/A71V and I50L/A71V double mutants is largely due to decreased binding entropy, which is compensated for by enhanced enthalpy for ATV binding to I50V variants and APV binding to I50L variants, leading to hypersusceptibility in these two cases. Analysis of the crystal structures showed that the substitutions at residue 50 affect how APV, DRV, and ATV bind the protease with altered van der Waals interactions and that the selection of I50V versus I50L is greatly influenced by the chemical moieties at the P1 position for APV/DRV and the P2 position for ATV. Thus, the varied inhibitor susceptibilities of I50V/L protease variants are largely a direct consequence of the interdependent changes in protease inhibitor interactions.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HIV-1 ProteaseA [auth B],
B [auth A],
C [auth D],
D [auth C]
99HIV-1 M:B_ARV2/SF2Mutation(s): 3 
Gene Names: gag-pol
EC: 3.4.23.16
UniProt
Find proteins for P03369 (Human immunodeficiency virus type 1 group M subtype B (isolate ARV2/SF2))
Explore P03369 
Go to UniProtKB:  P03369
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03369
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
017
Query on 017

Download Ideal Coordinates CCD File 
E [auth B],
Q [auth D]
(3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YL(1S,2R)-3-[[(4-AMINOPHENYL)SULFONYL](ISOBUTYL)AMINO]-1-BENZYL-2-HYDROXYPROPYLCARBAMATE
C27 H37 N3 O7 S
CJBJHOAVZSMMDJ-HEXNFIEUSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
F [auth B],
K [auth A],
R [auth C]
PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
GOL
Query on GOL

Download Ideal Coordinates CCD File 
J [auth B],
O [auth D],
P [auth D],
S [auth C]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
I [auth B],
M [auth A],
T [auth C],
U [auth C],
V [auth C]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
G [auth B],
H [auth B],
L [auth A],
N [auth D]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
017 BindingDB:  3OXW Ki: 0.25 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.175 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 50.62α = 90
b = 63.344β = 97.33
c = 58.648γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
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: 2011-09-28
    Type: Initial release
  • Version 1.1: 2015-04-01
    Changes: Database references
  • Version 1.2: 2017-11-08
    Changes: Refinement description
  • Version 1.3: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary