1MET

HIV-1 MUTANT (V82F) PROTEASE COMPLEXED WITH DMP323


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Work: 0.195 
  • R-Value Observed: 0.195 

wwPDB Validation   3D Report Full Report


This is version 1.5 of the entry. See complete history


Literature

Molecular basis of HIV-1 protease drug resistance: structural analysis of mutant proteases complexed with cyclic urea inhibitors.

Ala, P.J.Huston, E.E.Klabe, R.M.McCabe, D.D.Duke, J.L.Rizzo, C.J.Korant, B.D.DeLoskey, R.J.Lam, P.Y.Hodge, C.N.Chang, C.H.

(1997) Biochemistry 36: 1573-1580

  • DOI: https://doi.org/10.1021/bi962234u
  • Primary Citation of Related Structures:  
    1MER, 1MES, 1MET, 1MEU

  • PubMed Abstract: 

    In cell cultures, the key residues associated with HIV-1 resistance to cyclic urea-based HIV-1 protease (PR) inhibitors are Val82 and Ile84 of HIV-1 PR. To gain an understanding of how these two residues modulate inhibitor binding, we have measured the Ki values of three recombinant mutant proteases, I84V, V82F, and V82F/I84V, for DMP323 and DMP450, and determined the three-dimensional structures of their complexes to 2.1-1.9 A resolution with R factors of 18.7-19.6%. The Ki values of these mutants increased by 25-, 0.5-, and 1000-fold compared to the wild-type values of 0.8 and 0.4 nM for DMP323 and DMP450, respectively. The wild-type and mutant complexes overall are very similar (rms deviations of 0.2-0.3 A) except for differences in the patterns of their van der Waals (vdw) interactions, which appear to modulate the Ki values of the mutants. The loss of the CD1 atom of Ile84, in the I84V mutant complexes, creates a hole in the S1 subsite, reducing the number of vdw contacts and increasing the Ki values. The V82F mutant binds DMP323 more tightly than wild type because the side chain of Phe82 forms additional vdw and edge-to-face interactions with the P1 group of DMP323. The Ki values of the single mutants are not additive because the side chain of Phe82 rotates out of the S1 subsite in the double mutant (the chi 1 angles of Phe82 and -182 in the V82F and V82F/I84V mutants differ by 90 and 185 degrees, respectively), further reducing the vdw interactions. Finally, compensatory shifts in the I84V and V82F/ I84V complexes pick up a small number of new contacts, but too few to offset the initial loss of interactions caused by the mutations. Therefore, our data suggest that variants persist in the presence of DMP323 and DMP450 because of a decrease in vdw interactions between the mutant proteases and inhibitors.


  • Organizational Affiliation

    Department of Chemical and Physical Sciences, DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0024, USA.


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): 1 
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
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
DMP
Query on DMP

Download Ideal Coordinates CCD File 
C [auth A][4-R-(-4-ALPHA,5-ALPHA,6-BETA,7-BETA)]-HEXAHYDRO-5,6-BIS(HYDROXY)-[1,3-BIS([4-HYDROXYMETHYL-PHENYL]METHYL)-4,7-BIS(PHEN YLMETHYL)]-2H-1,3-DIAZEPINONE
C35 H38 N2 O5
XCVGQMUMMDXKCY-WZJLIZBTSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
DMP BindingDB:  1MET Ki: min: 0.27, max: 1 (nM) from 9 assay(s)
Kd: 3.83 (nM) from 1 assay(s)
IC50: min: 15, max: 110 (nM) from 2 assay(s)
Binding MOAD:  1MET Ki: 0.4 (nM) from 1 assay(s)
PDBBind:  1MET Ki: 0.4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Work: 0.195 
  • R-Value Observed: 0.195 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.8α = 90
b = 62.8β = 90
c = 83.5γ = 120
Software Package:
Software NamePurpose
X-PLORmodel building
X-PLORrefinement
X-PLORphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 1998-04-15
    Type: Initial release
  • Version 1.1: 2008-03-03
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-11-29
    Changes: Derived calculations, Other
  • Version 1.4: 2021-11-03
    Changes: Database references, Derived calculations, Structure summary
  • Version 1.5: 2023-08-09
    Changes: Refinement description