7BES

CryoEM structure of Mycobacterium tuberculosis UMP Kinase (UMPK) in complex with UDP and UTP


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 2.85 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structural basis for the allosteric inhibition of UMP kinase from Gram-positive bacteria, a promising antibacterial target.

Walter, P.Mechaly, A.Bous, J.Haouz, A.England, P.Lai-Kee-Him, J.Ancelin, A.Hoos, S.Baron, B.Trapani, S.Bron, P.Labesse, G.Munier-Lehmann, H.

(2022) FEBS J 289: 4869-4887

  • DOI: https://doi.org/10.1111/febs.16393
  • Primary Citation of Related Structures:  
    7BES, 7BIX, 7BL7

  • PubMed Abstract: 

    Tuberculosis claims significantly more than one million lives each year. A feasible way to face the issue of drug resistance is the development of new antibiotics. Bacterial uridine 5'-monophosphate (UMP) kinase is a promising target for novel antibiotic discovery as it is essential for bacterial survival and has no counterpart in human cells. The UMP kinase from M. tuberculosis is also a model of particular interest for allosteric regulation with two effectors, GTP (positive) and UTP (negative). In this study, using X-ray crystallography and cryo-electron microscopy, we report for the first time a detailed description of the negative effector UTP-binding site of a typical Gram-positive behaving UMP kinase. Comparison between this snapshot of low affinity for Mg-ATP with our previous 3D-structure of the GTP-bound complex of high affinity for Mg-ATP led to a better understanding of the cooperative mechanism and the allosteric regulation of UMP kinase. Thermal shift assay and circular dichroism experiments corroborate our model of an inhibition by UTP linked to higher flexibility of the Mg-ATP-binding domain. These new structural insights provide valuable knowledge for future drug discovery strategies targeting bacterial UMP kinases.


  • Organizational Affiliation

    Unité de Chimie et Biocatalyse, Département de Biologie Structurale et Chimie, Institut Pasteur, CNRS UMR3523, Paris, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Uridylate kinase
A, B, C
281Mycobacterium tuberculosisMutation(s): 0 
Gene Names: 
EC: 2.7.4.22
UniProt
Find proteins for P9WHK5 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WHK5 
Go to UniProtKB:  P9WHK5
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WHK5
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 2.85 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Marie Sklodowska-Curie Actions, FragNET ITNEuropean Union675555
Agence Nationale de la Recherche (ANR)FranceANR-10-INBS-05

Revision History  (Full details and data files)

  • Version 1.0: 2022-01-12
    Type: Initial release
  • Version 1.1: 2022-03-16
    Changes: Database references, Derived calculations
  • Version 1.2: 2022-08-24
    Changes: Database references
  • Version 1.3: 2024-07-10
    Changes: Data collection