5I6D

Mycobacterium tuberculosis CysM in complex with the Urea-scaffold inhibitor 5 [3-(3-(p-Tolyl)ureido) benzoic acid]


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.64 Å
  • R-Value Free: 0.186 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.165 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Inhibitors of the Cysteine Synthase CysM with Antibacterial Potency against Dormant Mycobacterium tuberculosis.

Brunner, K.Maric, S.Reshma, R.S.Almqvist, H.Seashore-Ludlow, B.Gustavsson, A.L.Poyraz, O.Yogeeswari, P.Lundback, T.Vallin, M.Sriram, D.Schnell, R.Schneider, G.

(2016) J Med Chem 59: 6848-6859

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b00674
  • Primary Citation of Related Structures:  
    5I6D, 5I7A, 5I7H, 5I7O, 5I7R, 5IW8, 5IWC

  • PubMed Abstract: 

    Cysteine is an important amino acid in the redox defense of Mycobacterium tuberculosis, primarily as a building block of mycothiol. Genetic studies have implicated de novo cysteine biosynthesis in pathogen survival in infected macrophages, in particular for persistent M. tuberculosis. Here, we report on the identification and characterization of potent inhibitors of CysM, a critical enzyme in cysteine biosynthesis during dormancy. A screening campaign of 17 312 compounds identified ligands that bind to the active site with micromolar affinity. These were characterized in terms of their inhibitory potencies and structure-activity relationships through hit expansion guided by three-dimensional structures of enzyme-inhibitor complexes. The top compound binds to CysM with 300 nM affinity and displays selectivity over the mycobacterial homologues CysK1 and CysK2. Notably, two inhibitors show significant potency in a nutrient-starvation model of dormancy of Mycobacterium tuberculosis, with little or no cytotoxicity toward mammalian cells.


  • Organizational Affiliation

    Division of Molecular Structural Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet , S-171 77 Stockholm, Sweden.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
O-phosphoserine sulfhydrylase
A, B, C, D
326Mycobacterium tuberculosisMutation(s): 1 
Gene Names: cysMRv1336MTCY130.21
EC: 2.5.1.113
UniProt
Find proteins for P9WP53 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WP53 
Go to UniProtKB:  P9WP53
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WP53
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
AU6
Query on AU6

Download Ideal Coordinates CCD File 
F [auth A],
I [auth B],
L [auth C],
N [auth D]
3-{[(4-methylphenyl)carbamoyl]amino}benzoic acid
C15 H14 N2 O3
TYCRWVKJQQIRNE-UHFFFAOYSA-N
PLP
Query on PLP

Download Ideal Coordinates CCD File 
E [auth A],
H [auth B],
K [auth C],
M [auth D]
PYRIDOXAL-5'-PHOSPHATE
C8 H10 N O6 P
NGVDGCNFYWLIFO-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
G [auth A],
J [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
AU6 Binding MOAD:  5I6D Kd: 8000 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.64 Å
  • R-Value Free: 0.186 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.165 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 64.552α = 94.57
b = 76.373β = 108.24
c = 80.865γ = 107.65
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Swedish Research CouncilSweden--

Revision History  (Full details and data files)

  • Version 1.0: 2016-08-17
    Type: Initial release
  • Version 1.1: 2017-09-13
    Changes: Author supporting evidence
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Refinement description