2AQU

Structure of HIV-1 protease bound to atazanavir


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.227 
  • R-Value Observed: 0.227 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Analysis of HIV-1 CRF_01 A/E protease inhibitor resistance: structural determinants for maintaining sensitivity and developing resistance to atazanavir.

Clemente, J.C.Coman, R.M.Thiaville, M.M.Janka, L.K.Jeung, J.A.Nukoolkarn, S.Govindasamy, L.Agbandje-McKenna, M.McKenna, R.Leelamanit, W.Goodenow, M.M.Dunn, B.M.

(2006) Biochemistry 45: 5468-5477

  • DOI: https://doi.org/10.1021/bi051886s
  • Primary Citation of Related Structures:  
    2AQU

  • PubMed Abstract: 

    A series of HIV-1 protease mutants has been designed in an effort to analyze the contribution to drug resistance provided by natural polymorphisms as well as therapy-selective (active and non-active site) mutations in the HIV-1 CRF_01 A/E (AE) protease when compared to that of the subtype B (B) protease. Kinetic analysis of these variants using chromogenic substrates showed differences in substrate specificity between pretherapy B and AE proteases. Inhibition analysis with ritonavir, indinavir, nelfinavir, amprenavir, saquinavir, lopinavir, and atazanavir revealed that the natural polymorphisms found in A/E can influence inhibitor resistance. It was also apparent that a high level of resistance in the A/E protease, as with B protease, is due to it aquiring a combination of active site and non-active site mutations. Structural analysis of atazanavir bound to a pretherapy B protease showed that the ability of atazanavir to maintain its binding affinity for variants containing some resistance mutations is due to its unique interactions with flap residues. This structure also explains why the I50L and I84V mutations are important in decreasing the binding affinity of atazanavir.


  • Organizational Affiliation

    Johnson & Johnson Pharmaceutical Research & Development, LLC, 665 Stockton Drive, Exton, Pennsylvania 19341, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HIV-1 Protease
A, B
99Human immunodeficiency virus 1Mutation(s): 0 
EC: 3.4.23.16
UniProt
Find proteins for P03366 (Human immunodeficiency virus type 1 group M subtype B (isolate BH10))
Explore P03366 
Go to UniProtKB:  P03366
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03366
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
DR7
Query on DR7

Download Ideal Coordinates CCD File 
C [auth B](3S,8S,9S,12S)-3,12-BIS(1,1-DIMETHYLETHYL)-8-HYDROXY-4,11-DIOXO-9-(PHENYLMETHYL)-6-[[4-(2-PYRIDINYL)PHENYL]METHYL]-2,5, 6,10,13-PENTAAZATETRADECANEDIOIC ACID DIMETHYL ESTER
C38 H52 N6 O7
AXRYRYVKAWYZBR-GASGPIRDSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
DR7 BindingDB:  2AQU Ki: min: 9.00e-3, max: 50 (nM) from 14 assay(s)
Kd: 0.4 (nM) from 1 assay(s)
IC50: min: 0.04, max: 40 (nM) from 5 assay(s)
EC50: 0.7 (nM) from 1 assay(s)
Binding MOAD:  2AQU Ki: 0.48 (nM) from 1 assay(s)
PDBBind:  2AQU Ki: 0.48 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.227 
  • R-Value Observed: 0.227 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.411α = 90
b = 62.411β = 90
c = 82.569γ = 120
Software Package:
Software NamePurpose
CNSrefinement
SCALEPACKdata scaling
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2006-08-29
    Type: Initial release
  • Version 1.1: 2008-04-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Derived calculations, Version format compliance
  • Version 1.3: 2023-08-23
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary