2F80

HIV-1 Protease mutant D30N complexed with inhibitor TMC114


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.149 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Effectiveness of Nonpeptide Clinical Inhibitor TMC-114 on HIV-1 Protease with Highly Drug Resistant Mutations D30N, I50V, and L90M.

Kovalevsky, A.Y.Tie, Y.Liu, F.Boross, P.I.Wang, Y.F.Leshchenko, S.Ghosh, A.K.Harrison, R.W.Weber, I.T.

(2006) J Med Chem 49: 1379-1387

  • DOI: https://doi.org/10.1021/jm050943c
  • Primary Citation of Related Structures:  
    2F80, 2F81, 2F8G

  • PubMed Abstract: 

    The potent new antiviral inhibitor TMC-114 (UIC-94017) of HIV-1 protease (PR) has been studied with three PR variants containing single mutations D30N, I50V, and L90M, which provide resistance to the major clinical inhibitors. The inhibition constants (K(i)) of TMC-114 for mutants PR(D30N), PR(I50V), and PR(L90M) were 30-, 9-, and 0.14-fold, respectively, relative to wild-type PR. The molecular basis for the inhibition was analyzed using high-resolution (1.22-1.45 A) crystal structures of PR mutant complexes with TMC-114. In PR(D30N), the inhibitor has a water-mediated interaction with the side chain of Asn30 rather than the direct interaction observed in PR, which is consistent with the relative inhibition. Similarly, in PR(I50V) the inhibitor loses favorable hydrophobic interactions with the side chain of Val50. TMC-114 has additional van der Waals contacts in PR(L90M) structure compared to the PR structure, leading to a tighter binding of the inhibitor. The observed changes in PR structure and activity are discussed in relation to the potential for development of resistant mutants on exposure to TMC-114.


  • Organizational Affiliation

    Department of Biology, Molecular Basis of Disease, Georgia State University, Atlanta, Georgia 30303, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
POL POLYPROTEIN
A, B
99Human immunodeficiency virus 1Mutation(s): 6 
Gene Names: POL
EC: 3.4.23.16
UniProt
Find proteins for P04587 (Human immunodeficiency virus type 1 group M subtype B (isolate BH5))
Explore P04587 
Go to UniProtKB:  P04587
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04587
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
017
Query on 017

Download Ideal Coordinates CCD File 
F [auth B](3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YL(1S,2R)-3-[[(4-AMINOPHENYL)SULFONYL](ISOBUTYL)AMINO]-1-BENZYL-2-HYDROXYPROPYLCARBAMATE
C27 H37 N3 O7 S
CJBJHOAVZSMMDJ-HEXNFIEUSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
E [auth B]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
CL
Query on CL

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
017 BindingDB:  2F80 Ki: min: 2.00e-4, max: 2 (nM) from 16 assay(s)
Kd: 0.02 (nM) from 1 assay(s)
IC50: min: 0.06, max: 370 (nM) from 10 assay(s)
EC50: min: 0.25, max: 112 (nM) from 4 assay(s)
Binding MOAD:  2F80 Ki: 6.6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.149 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.492α = 90
b = 86.134β = 90
c = 45.943γ = 90
Software Package:
Software NamePurpose
SHELXmodel building
SHELXL-97refinement
MAR345data collection
SCALEPACKdata scaling
AMoREphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-03-07
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 1.3: 2017-10-18
    Changes: Refinement description
  • Version 1.4: 2021-10-20
    Changes: Database references, Derived calculations, Structure summary
  • Version 1.5: 2024-02-14
    Changes: Data collection