1RV7

Crystal structures of a Multidrug-Resistant HIV-1 Protease Reveal an Expanded Active Site Cavity


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.350 
  • R-Value Work: 0.271 
  • R-Value Observed: 0.271 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Crystal structures of a multidrug-resistant human immunodeficiency virus type 1 protease reveal an expanded active-site cavity.

Logsdon, B.C.Vickrey, J.F.Martin, P.Proteasa, G.Koepke, J.I.Terlecky, S.R.Wawrzak, Z.Winters, M.A.Merigan, T.C.Kovari, L.C.

(2004) J Virol 78: 3123-3132

  • DOI: https://doi.org/10.1128/jvi.78.6.3123-3132.2004
  • Primary Citation of Related Structures:  
    1RPI, 1RQ9, 1RV7

  • PubMed Abstract: 

    The goal of this study was to use X-ray crystallography to investigate the structural basis of resistance to human immunodeficiency virus type 1 (HIV-1) protease inhibitors. We overexpressed, purified, and crystallized a multidrug-resistant (MDR) HIV-1 protease enzyme derived from a patient failing on several protease inhibitor-containing regimens. This HIV-1 variant contained codon mutations at positions 10, 36, 46, 54, 63, 71, 82, 84, and 90 that confer drug resistance to protease inhibitors. The 1.8-angstrom (A) crystal structure of this MDR patient isolate reveals an expanded active-site cavity. The active-site expansion includes position 82 and 84 mutations due to the alterations in the amino acid side chains from longer to shorter (e.g., V82A and I84V). The MDR isolate 769 protease "flaps" stay open wider, and the difference in the flap tip distances in the MDR 769 variant is 12 A. The MDR 769 protease crystal complexes with lopinavir and DMP450 reveal completely different binding modes. The network of interactions between the ligands and the MDR 769 protease is completely different from that seen with the wild-type protease-ligand complexes. The water molecule-forming hydrogen bonds bridging between the two flaps and either the substrate or the peptide-based inhibitor are lacking in the MDR 769 clinical isolate. The S1, S1', S3, and S3' pockets show expansion and conformational change. Surface plasmon resonance measurements with the MDR 769 protease indicate higher k(off) rates, resulting in a change of binding affinity. Surface plasmon resonance measurements provide k(on) and k(off) data (K(d) = k(off)/k(on)) to measure binding of the multidrug-resistant protease to various ligands. This MDR 769 protease represents a new antiviral target, presenting the possibility of designing novel inhibitors with activity against the open and expanded protease forms.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, 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): 3 
Gene Names: HIV-1
EC: 3.4.23.16
UniProt
Find proteins for Q9QM22 (Human immunodeficiency virus 1)
Explore Q9QM22 
Go to UniProtKB:  Q9QM22
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9QM22
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
AB1
Query on AB1

Download Ideal Coordinates CCD File 
C [auth B]N-{1-BENZYL-4-[2-(2,6-DIMETHYL-PHENOXY)-ACETYLAMINO]-3-HYDROXY-5-PHENYL-PENTYL}-3-METHYL-2-(2-OXO-TETRAHYDRO-PYRIMIDIN-1-YL)-BUTYRAMIDE
C37 H48 N4 O5
KJHKTHWMRKYKJE-SUGCFTRWSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
AB1 BindingDB:  1RV7 Ki: min: 5.00e-3, max: 16 (nM) from 7 assay(s)
Kd: 1.30e-3 (nM) from 1 assay(s)
IC50: min: 2.5, max: 25 (nM) from 2 assay(s)
EC50: 1160 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.350 
  • R-Value Work: 0.271 
  • R-Value Observed: 0.271 
  • Space Group: P 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 44.975α = 90
b = 44.975β = 90
c = 103.676γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
CrystalCleardata reduction
d*TREKdata scaling

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-12-14
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2021-10-27
    Changes: Database references, Derived calculations, Structure summary
  • Version 1.4: 2024-02-14
    Changes: Data collection