1MRS

CRYSTAL STRUCTURE OF MYCOBACTERIUM TUBERCULOSIS THYMIDYLATE KINASE COMPLEXED WITH 5-CH2OH DEOXYURIDINE MONOPHOSPHATE


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.265 
  • R-Value Work: 0.228 
  • R-Value Observed: 0.232 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Enzymatic and structural analysis of inhibitors designed against Mycobacterium tuberculosis thymidylate kinase. New insights into the phosphoryl transfer mechanism.

Haouz, A.Vanheusden, V.Munier-Lehmann, H.Froeyen, M.

(2003) J Biol Chem 278: 4963-4971

  • DOI: https://doi.org/10.1074/jbc.M209630200
  • Primary Citation of Related Structures:  
    1MRN, 1MRS

  • PubMed Abstract: 

    The chemical synthesis of new compounds designed as inhibitors of Mycobacterium tuberculosis TMP kinase (TMPK) is reported. The synthesis concerns TMP analogues modified at the 5-position of the thymine ring as well as a novel compound with a six-membered sugar ring. The binding properties of the analogues are compared with the known inhibitor azido-TMP, which is postulated here to work by excluding the TMP-bound Mg(2+) ion. The crystallographic structure of the complex of one of the compounds, 5-CH(2)OH-dUMP, with TMPK has been determined at 2.0 A. It reveals a major conformation for the hydroxyl group in contact with a water molecule and a minor conformation pointing toward Ser(99). Looking for a role for Ser(99), we have identified an unusual catalytic triad, or a proton wire, made of strictly conserved residues (including Glu(6), Ser(99), Arg(95), and Asp(9)) that probably serves to protonate the transferred PO(3) group. The crystallographic structure of the commercially available bisubstrate analogue P(1)-(adenosine-5')-P(5)-(thymidine-5')-pentaphosphate bound to TMPK is also reported at 2.45 A and reveals an alternative binding pocket for the adenine moiety of the molecule compared with what is observed either in the Escherichia coli or in the yeast enzyme structures. This alternative binding pocket opens a way for the design of a new family of specific inhibitors.


  • Organizational Affiliation

    Unité de Biochimie Structurale, URA 2185 du CNRS, Biologie Structurale et Agents Infectieux, Institut Pasteur, 25 rue du Dr Roux, 75015 Paris, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
THYMIDYLATE KINASE214Mycobacterium tuberculosisMutation(s): 0 
EC: 2.7.4.9
UniProt
Find proteins for P9WKE1 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WKE1 
Go to UniProtKB:  P9WKE1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WKE1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
5HU Binding MOAD:  1MRS Ki: 1.10e+5 (nM) from 1 assay(s)
PDBBind:  1MRS Ki: 1.10e+5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.265 
  • R-Value Work: 0.228 
  • R-Value Observed: 0.232 
  • Space Group: P 65 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 76.4α = 90
b = 76.4β = 90
c = 134.4γ = 120
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2003-01-07
    Type: Initial release
  • Version 1.1: 2008-04-28
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2024-02-14
    Changes: Data collection, Database references, Derived calculations, Refinement description