3LZU

Crystal Structure of a Nelfinavir Resistant HIV-1 CRF01_AE Protease variant (N88S) in Complex with the Protease Inhibitor Darunavir.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.76 Å
  • R-Value Free: 0.239 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.198 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

The Effect of Clade-Specific Sequence Polymorphisms on HIV-1 Protease Activity and Inhibitor Resistance Pathways.

Bandaranayake, R.M.Kolli, M.King, N.M.Nalivaika, E.A.Heroux, A.Kakizawa, J.Sugiura, W.Schiffer, C.A.

(2010) J Virol 84: 9995-10003

  • DOI: https://doi.org/10.1128/JVI.00505-10
  • Primary Citation of Related Structures:  
    3LZS, 3LZU, 3LZV

  • PubMed Abstract: 

    The majority of HIV-1 infections around the world result from non-B clade HIV-1 strains. The CRF01_AE (AE) strain is seen principally in Southeast Asia. AE protease differs by approximately 10% in amino acid sequence from clade B protease and carries several naturally occurring polymorphisms that are associated with drug resistance in clade B. AE protease has been observed to develop resistance through a nonactive-site N88S mutation in response to nelfinavir (NFV) therapy, whereas clade B protease develops both the active-site mutation D30N and the nonactive-site mutation N88D. Structural and biochemical studies were carried out with wild-type and NFV-resistant clade B and AE protease variants. The relationship between clade-specific sequence variations and pathways to inhibitor resistance was also assessed. AE protease has a lower catalytic turnover rate than clade B protease, and it also has weaker affinity for both NFV and darunavir (DRV). This weaker affinity may lead to the nonactive-site N88S variant in AE, which exhibits significantly decreased affinity for both NFV and DRV. The D30N/N88D mutations in clade B resulted in a significant loss of affinity for NFV and, to a lesser extent, for DRV. A comparison of crystal structures of AE protease shows significant structural rearrangement in the flap hinge region compared with those of clade B protease and suggests insights into the alternative pathways to NFV resistance. In combination, our studies show that sequence polymorphisms within clades can alter protease activity and inhibitor binding and are capable of altering the pathway to inhibitor resistance.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, 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]
99Human immunodeficiency virus 1Mutation(s): 2 
Gene Names: gag-pol
EC: 3.4.23.16
UniProt
Find proteins for P24740 (Human immunodeficiency virus type 1 group M subtype A (isolate U455))
Explore P24740 
Go to UniProtKB:  P24740
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP24740
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
017 BindingDB:  3LZU Ki: min: 2.00e-4, max: 2 (nM) from 17 assay(s)
Kd: 0.02 (nM) from 1 assay(s)
IC50: min: 0.06, max: 370 (nM) from 11 assay(s)
EC50: min: 0.18, max: 112 (nM) from 5 assay(s)
Binding MOAD:  3LZU Kd: 0.09 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.76 Å
  • R-Value Free: 0.239 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.198 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 61.878α = 90
b = 61.878β = 90
c = 82.15γ = 120
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
REFMACrefinement
PDB_EXTRACTdata extraction
BioCARSdata collection
HKL-2000data reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-08-11
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-08
    Changes: Refinement description
  • Version 1.3: 2021-10-13
    Changes: Database references, Derived calculations, Structure summary
  • Version 1.4: 2023-09-06
    Changes: Data collection, Refinement description