4YOB

Crystal Structure of Apo HIV-1 Protease MDR769 L33F


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.194 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.177 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

The L33F darunavir resistance mutation acts as a molecular anchor reducing the flexibility of the HIV-1 protease 30s and 80s loops.

Kuiper, B.D.Keusch, B.J.Dewdney, T.G.Chordia, P.Ross, K.Brunzelle, J.S.Kovari, I.A.MacArthur, R.Salimnia, H.Kovari, L.C.

(2015) Biochem Biophys Rep 2: 160-165

  • DOI: https://doi.org/10.1016/j.bbrep.2015.06.003
  • Primary Citation of Related Structures:  
    4YOA, 4YOB

  • PubMed Abstract: 

    HIV-1 protease (PR) is a 99 amino acid protein responsible for proteolytic processing of the viral polyprotein - an essential step in the HIV-1 life cycle. Drug resistance mutations in PR that are selected during antiretroviral therapy lead to reduced efficacy of protease inhibitors (PI) including darunavir (DRV). To identify the structural mechanisms associated with the DRV resistance mutation L33F, we performed X-ray crystallographic studies with a multi-drug resistant HIV-1 protease isolate that contains the L33F mutation (MDR769 L33F). In contrast to other PR L33F DRV complexes, the structure of MDR769 L33F complexed with DRV reported here displays the protease flaps in an open conformation. The L33F mutation increases noncovalent interactions in the hydrophobic pocket of the PR compared to the wild-type (WT) structure. As a result, L33F appears to act as a molecular anchor, reducing the flexibility of the 30s loop (residues 29-35) and the 80s loop (residues 79-84). Molecular anchoring of the 30s and 80s loops leaves an open S1/S1' subsite and distorts the conserved hydrogen-bonding network of DRV. These findings are consistent with previous reports despite structural differences with regards to flap conformation.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HIV-1 Protease99Human immunodeficiency virus 1Mutation(s): 6 
Gene Names: pol
UniProt
Find proteins for Q5RTL1 (Human immunodeficiency virus 1)
Explore Q5RTL1 
Go to UniProtKB:  Q5RTL1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ5RTL1
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.194 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.177 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.754α = 90
b = 45.754β = 90
c = 102.22γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement

Structure Validation

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United States--

Revision History  (Full details and data files)

  • Version 1.0: 2015-07-08
    Type: Initial release
  • Version 1.1: 2018-04-18
    Changes: Data collection, Database references, Derived calculations, Source and taxonomy
  • Version 1.2: 2022-03-30
    Changes: Author supporting evidence, Database references
  • Version 1.3: 2024-02-28
    Changes: Data collection