3EKY

Crystal Structure of wild-type HIV protease in complex with the inhibitor, Atazanavir


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.177 

Starting Model: experimental
View more details

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.6 of the entry. See complete history


Literature

Extreme Entropy-Enthalpy Compensation in a Drug-Resistant Variant of HIV-1 Protease.

King, N.M.Prabu-Jeyabalan, M.Bandaranayake, R.M.Nalam, M.N.Nalivaika, E.A.Ozen, A.Yilmaz, N.K.Schiffer, C.A.

(2012) ACS Chem Biol 7: 1536-1546

  • DOI: https://doi.org/10.1021/cb300191k
  • Primary Citation of Related Structures:  
    3EKP, 3EKQ, 3EKT, 3EKV, 3EKW, 3EKX, 3EKY, 3EL0, 3EL1, 3EL4, 3EL5, 3EL9

  • PubMed Abstract: 

    The development of HIV-1 protease inhibitors has been the historic paradigm of rational structure-based drug design, where structural and thermodynamic analyses have assisted in the discovery of novel inhibitors. While the total enthalpy and entropy change upon binding determine the affinity, often the thermodynamics are considered in terms of inhibitor properties only. In the current study, profound changes are observed in the binding thermodynamics of a drug-resistant variant compared to wild-type HIV-1 protease, irrespective of the inhibitor bound. This variant (Flap+) has a combination of flap and active site mutations and exhibits extremely large entropy-enthalpy compensation compared to wild-type protease, 5-15 kcal/mol, while losing only 1-3 kcal/mol in total binding free energy for any of six FDA-approved inhibitors. Although entropy-enthalpy compensation has been previously observed for a variety of systems, never have changes of this magnitude been reported. The co-crystal structures of Flap+ protease with four of the inhibitors were determined and compared with complexes of both the wild-type protease and another drug-resistant variant that does not exhibit this energetic compensation. Structural changes conserved across the Flap+ complexes, which are more pronounced for the flaps covering the active site, likely contribute to the thermodynamic compensation. The finding that drug-resistant mutations can profoundly modulate the relative thermodynamic properties of a therapeutic target independent of the inhibitor presents a new challenge for rational drug design.


  • 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
Protease
A, B
99HIV-1 M:B_ARV2/SF2Mutation(s): 2 
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
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
DR7 BindingDB:  3EKY Ki: min: 9.00e-3, max: 1.1 (nM) from 4 assay(s)
PDBBind:  3EKY Kd: 0.23 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.177 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 50.862α = 90
b = 58.099β = 90
c = 61.999γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
SCALEPACKdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-09-01
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2012-07-25
    Changes: Database references
  • Version 1.3: 2012-10-17
    Changes: Database references
  • Version 1.4: 2017-10-25
    Changes: Refinement description
  • Version 1.5: 2021-10-20
    Changes: Database references, Derived calculations, Structure summary
  • Version 1.6: 2023-08-30
    Changes: Data collection, Refinement description