1F6T

STRUCTURE OF THE NUCLEOSIDE DIPHOSPHATE KINASE/ALPHA-BORANO(RP)-TDP.MG COMPLEX


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.92 Å
  • R-Value Free: 0.274 
  • R-Value Work: 0.228 
  • R-Value Observed: 0.228 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structural basis for activation of alpha-boranophosphate nucleotide analogues targeting drug-resistant reverse transcriptase.

Meyer, P.Schneider, B.Sarfati, S.Deville-Bonne, D.Guerreiro, C.Boretto, J.Janin, J.Veron, M.Canard, B.

(2000) EMBO J 19: 3520-3529

  • DOI: https://doi.org/10.1093/emboj/19.14.3520
  • Primary Citation of Related Structures:  
    1F3F, 1F6T

  • PubMed Abstract: 

    AIDS chemotherapy is limited by inadequate intracellular concentrations of the active triphosphate form of nucleoside analogues, leading to incomplete inhibition of viral replication and the appearance of drug-resistant virus. Drug activation by nucleoside diphosphate kinase and inhibition of HIV-1 reverse transcriptase were studied comparatively. We synthesized analogues with a borano (BH(3)(-)) group on the alpha-phosphate, and found that they are substrates for both enzymes. X-ray structures of complexes with nucleotide diphosphate kinase provided a structural basis for their activation. The complex with d4T triphosphate displayed an intramolecular CH.O bond contributing to catalysis, and the R(p) diastereoisomer of thymidine alpha-boranotriphosphate bound like a normal substrate. Using alpha-(R(p))-boranophosphate derivatives of the clinically relevant compounds AZT and d4T, the presence of the alpha-borano group improved both phosphorylation by nucleotide diphosphate kinase and inhibition of reverse transcription. Moreover, repair of blocked DNA chains by pyrophosphorolysis was reduced significantly in variant reverse transcriptases bearing substitutions found in drug-resistant viruses. Thus, the alpha-borano modification of analogues targeting reverse transcriptase may be of generic value in fighting viral drug resistance.


  • Organizational Affiliation

    Laboratoire d'Enzymologie et Biochimie Structurales, UPR-9063 CNRS, 91198 Gif-sur-Yvette, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
PROTEIN (NUCLEOSIDE DIPHOSPHATE KINASE)
A, B, C
155Dictyostelium discoideumMutation(s): 0 
EC: 2.7.4.6
UniProt
Find proteins for P22887 (Dictyostelium discoideum)
Explore P22887 
Go to UniProtKB:  P22887
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP22887
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.92 Å
  • R-Value Free: 0.274 
  • R-Value Work: 0.228 
  • R-Value Observed: 0.228 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 70.359α = 90
b = 70.359β = 90
c = 153.792γ = 120
Software Package:
Software NamePurpose
AMoREphasing
CNSrefinement
MOSFLMdata reduction
CCP4data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2000-09-13
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Derived calculations, Version format compliance
  • Version 1.3: 2024-02-07
    Changes: Data collection, Database references, Derived calculations