4OBH

Crystal Structure of Inactive HIV-1 Protease in Complex with the p1-p6 substrate variant (L449F)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.161 
  • R-Value Observed: 0.163 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

HIV-1 protease-substrate coevolution in nelfinavir resistance.

Kolli, M.Ozen, A.Kurt-Yilmaz, N.Schiffer, C.A.

(2014) J Virol 88: 7145-7154

  • DOI: https://doi.org/10.1128/JVI.00266-14
  • Primary Citation of Related Structures:  
    4OBD, 4OBF, 4OBG, 4OBH, 4OBJ, 4OBK

  • PubMed Abstract: 

    Resistance to various human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) challenges the effectiveness of therapies in treating HIV-1-infected individuals and AIDS patients. The virus accumulates mutations within the protease (PR) that render the PIs less potent. Occasionally, Gag sequences also coevolve with mutations at PR cleavage sites contributing to drug resistance. In this study, we investigated the structural basis of coevolution of the p1-p6 cleavage site with the nelfinavir (NFV) resistance D30N/N88D protease mutations by determining crystal structures of wild-type and NFV-resistant HIV-1 protease in complex with p1-p6 substrate peptide variants with L449F and/or S451N. Alterations of residue 30's interaction with the substrate are compensated by the coevolving L449F and S451N cleavage site mutations. This interdependency in the PR-p1-p6 interactions enhances intermolecular contacts and reinforces the overall fit of the substrate within the substrate envelope, likely enabling coevolution to sustain substrate recognition and cleavage in the presence of PR resistance mutations.


  • 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 Protease
A, B, C, D
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
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
p1-p6 peptide
E, F
10Human immunodeficiency virus 1Mutation(s): 1 
UniProt
Find proteins for P03349 (Human immunodeficiency virus type 1 group M subtype B (isolate ARV2/SF2))
Explore P03349 
Go to UniProtKB:  P03349
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03349
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
PO4
Query on PO4

Download Ideal Coordinates CCD File 
Z [auth D]PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
GOL
Query on GOL

Download Ideal Coordinates CCD File 
AA [auth E]
G [auth A]
H [auth A]
J [auth A]
T [auth D]
AA [auth E],
G [auth A],
H [auth A],
J [auth A],
T [auth D],
U [auth D]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
I [auth A]
K [auth A]
L [auth A]
M [auth A]
N [auth B]
I [auth A],
K [auth A],
L [auth A],
M [auth A],
N [auth B],
O [auth B],
Q [auth C],
R [auth C],
S [auth C],
V [auth D],
W [auth D],
X [auth D],
Y [auth D]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
P [auth C]ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.161 
  • R-Value Observed: 0.163 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.144α = 90
b = 62.787β = 98.03
c = 58.537γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
BioCARS-developeddata collection
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2014-11-26 
  • Deposition Author(s): Kolli, M.

Revision History  (Full details and data files)

  • Version 1.0: 2014-11-26
    Type: Initial release
  • Version 1.1: 2017-11-22
    Changes: Refinement description
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description