3VFB

Crystal Structure of HIV-1 Protease Mutant N88D with novel P1'-Ligands GRL-02031


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.55 Å
  • R-Value Free: 0.216 
  • R-Value Observed: 0.158 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Potent antiviral HIV-1 protease inhibitor GRL-02031 adapts to the structures of drug resistant mutants with its P1'-pyrrolidinone ring.

Chang, Y.C.Yu, X.Zhang, Y.Tie, Y.Wang, Y.F.Yashchuk, S.Ghosh, A.K.Harrison, R.W.Weber, I.T.

(2012) J Med Chem 55: 3387-3397

  • DOI: https://doi.org/10.1021/jm300072d
  • Primary Citation of Related Structures:  
    3VF5, 3VF7, 3VFA, 3VFB

  • PubMed Abstract: 

    GRL-02031 (1) is an HIV-1 protease (PR) inhibitor containing a novel P1' (R)-aminomethyl-2-pyrrolidinone group. Crystal structures at resolutions of 1.25-1.55 Å were analyzed for complexes of 1 with the PR containing major drug resistant mutations, PR(I47V), PR(L76V), PR(V82A), and PR(N88D). Mutations of I47V and V82A alter residues in the inhibitor-binding site, while L76V and N88D are distal mutations having no direct contact with the inhibitor. Substitution of a smaller amino acid in PR(I47V) and PR(L76V) and the altered charge of PR(N88D) are associated with significant local structural changes compared to the wild-type PR(WT), while substitution of alanine in PR(V82A) increases the size of the S1' subsite. The P1' pyrrolidinone group of 1 accommodates to these local changes by assuming two different conformations. Overall, the conformation and interactions of 1 with PR mutants resemble those of PR(WT) with similar inhibition constants in good agreement with the antiviral potency on multidrug resistant HIV-1.


  • Organizational Affiliation

    Department of Biology, Molecular Basis of Disease Program, Georgia State University, P.O. Box 4010, Atlanta, Georgia 30302-4010, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
protease
A, B
99Human immunodeficiency virus type 1 (BRU ISOLATE)Mutation(s): 6 
Gene Names: gag-pol
EC: 3.4.23.16
UniProt
Find proteins for P03367 (Human immunodeficiency virus type 1 group M subtype B (isolate BRU/LAI))
Explore P03367 
Go to UniProtKB:  P03367
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03367
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
031
Query on 031

Download Ideal Coordinates CCD File 
C [auth A](3aS,5R,6aR)-hexahydro-2H-cyclopenta[b]furan-5-yl [(1S,2R)-1-benzyl-2-hydroxy-3-([(4-methoxyphenyl)sulfonyl]{[(2R)-5-oxopyrrolidin-2-yl]methyl}amino)propyl]carbamate
C30 H39 N3 O8 S
RPIALZPTIFOQGC-CXLNPQPMSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
G [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
D [auth A],
I [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
NA
Query on NA

Download Ideal Coordinates CCD File 
H [auth B]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
031 BindingDB:  3VFB Ki: min: 0.1, max: 0.44 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.55 Å
  • R-Value Free: 0.216 
  • R-Value Observed: 0.158 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.255α = 90
b = 86.386β = 90
c = 46.068γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
MOLREPphasing
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: 2012-11-21
    Type: Initial release
  • Version 1.1: 2012-11-28
    Changes: Data collection
  • Version 1.2: 2015-03-25
    Changes: Database references
  • Version 1.3: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description