2AZB

HIV-1 Protease NL4-3 3X mutant in complex with inhibitor, TL-3


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.03 Å
  • R-Value Free: 0.287 
  • R-Value Work: 0.219 
  • R-Value Observed: 0.219 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.7 of the entry. See complete history


Literature

Structural Insights into the Mechanisms of Drug Resistance in HIV-1 Protease NL4-3

Heaslet, H.Kutilek, V.Morris, G.M.Lin, Y.-C.Elder, J.H.Torbett, B.E.Stout, C.D.

(2006) J Mol Biol 356: 967-981

  • DOI: https://doi.org/10.1016/j.jmb.2005.11.094
  • Primary Citation of Related Structures:  
    2AZ8, 2AZ9, 2AZB, 2AZC

  • PubMed Abstract: 

    The development of resistance to anti-retroviral drugs targeted against HIV is an increasing clinical problem in the treatment of HIV-1-infected individuals. Many patients develop drug-resistant strains of the virus after treatment with inhibitor cocktails (HAART therapy), which include multiple protease inhibitors. Therefore, it is imperative that we understand the mechanisms by which the viral proteins, in particular HIV-1 protease, develop resistance. We have determined the three-dimensional structure of HIV-1 protease NL4-3 in complex with the potent protease inhibitor TL-3 at 2.0 A resolution. We have also obtained the crystal structures of three mutant forms of NL4-3 protease containing one (V82A), three (V82A, M46I, F53L) and six (V82A, M46I, F53L, V77I, L24I, L63P) point mutations in complex with TL-3. The three protease mutants arose sequentially under ex vivo selective pressure in the presence of TL-3, and exhibit fourfold, 11-fold, and 30-fold resistance to TL-3, respectively. This series of protease crystal structures offers insights into the biochemical and structural mechanisms by which the enzyme can overcome inhibition by TL-3 while recovering some of its native catalytic activity.


  • Organizational Affiliation

    Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA. [email protected]


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
PROTEASE RETROPEPSIN99Human immunodeficiency virus 1Mutation(s): 5 
Gene Names: 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
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3TL
Query on 3TL

Download Ideal Coordinates CCD File 
B [auth A]benzyl [(1S,4S,7S,8R,9R,10S,13S,16S)-7,10-dibenzyl-8,9-dihydroxy-1,16-dimethyl-4,13-bis(1-methylethyl)-2,5,12,15,18-pentaoxo-20-phenyl-19-oxa-3,6,11,14,17-pentaazaicos-1-yl]carbamate
C50 H64 N6 O10
BJJPNOGMLLUCER-KUTQPOQPSA-N
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.03 Å
  • R-Value Free: 0.287 
  • R-Value Work: 0.219 
  • R-Value Observed: 0.219 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.539α = 90
b = 62.539β = 90
c = 81.852γ = 120
Software Package:
Software NamePurpose
MAR345data collection
MOSFLMdata reduction
MOLREPphasing
CNSrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-02-28
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Structure summary, Version format compliance
  • Version 1.3: 2013-02-27
    Changes: Other
  • Version 1.4: 2017-10-11
    Changes: Advisory, Refinement description
  • Version 1.5: 2018-01-24
    Changes: Database references, Structure summary
  • Version 1.6: 2021-10-20
    Changes: Advisory, Database references, Derived calculations
  • Version 1.7: 2023-08-23
    Changes: Data collection, Refinement description