2UUP

Crystal structure of MurD ligase in complex with D-Glu containing sulfonamide inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.88 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.184 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Novel naphthalene-N-sulfonyl-D-glutamic acid derivatives as inhibitors of MurD, a key peptidoglycan biosynthesis enzyme.

Humljan, J.Kotnik, M.Contreras-Martel, C.Blanot, D.Urleb, U.Dessen, A.Solmajer, T.Gobec, S.

(2008) J Med Chem 51: 7486-7494

  • DOI: https://doi.org/10.1021/jm800762u
  • Primary Citation of Related Structures:  
    2UUO, 2UUP, 2VTD, 2VTE

  • PubMed Abstract: 

    Mur ligases have essential roles in the biosynthesis of peptidoglycan, and they represent attractive targets for the design of novel antibacterials. MurD (UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase) is the second enzyme in the series of Mur ligases, and it catalyzes the addition of D-glutamic acid (D-Glu) to the cytoplasmic intermediate UDP-N-acetylmuramoyl-L-alanine (UMA). Because of the high binding affinity of D-Glu toward MurD, we synthesized and biochemically evaluated a series of N-substituted D-Glu derivatives as potential inhibitors of MurD from E. coli, which allowed us to explore the structure-activity relationships.The substituted naphthalene-N-sulfonyl-D-Glu inhibitors, which were synthesized as potential transition state analogues, displayed IC50 values ranging from 80 to 600 microM. In addition, the high-resolution crystal structures of MurD in complex with four novel inhibitors revealed details of the binding mode of the inhibitors within the active site of MurD. Structure-activity relationships and cocrystal structures constitute an excellent starting point for further development of novel MurD inhibitors of this structural class.


  • Organizational Affiliation

    Drug Discovery, Lek Pharmaceuticals d.d., Verovskova 57, 1526 Ljubljana, Slovenia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
UDP-N-ACETYLMURAMOYLALANINE--D-GLUTAMATE LIGASE445Escherichia coliMutation(s): 0 
EC: 6.3.2.9
UniProt
Find proteins for P14900 (Escherichia coli (strain K12))
Explore P14900 
Go to UniProtKB:  P14900
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP14900
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
KCX
Query on KCX
A
L-PEPTIDE LINKINGC7 H14 N2 O4LYS
Binding Affinity Annotations 
IDSourceBinding Affinity
LK4 PDBBind:  2UUP IC50: 1.05e+5 (nM) from 1 assay(s)
Binding MOAD:  2UUP IC50: 1.05e+5 (nM) from 1 assay(s)
BindingDB:  2UUP IC50: 1.05e+5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.88 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.184 
  • Space Group: P 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 65.517α = 90
b = 65.517β = 90
c = 136.174γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-03-25
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2018-01-31
    Changes: Database references, Source and taxonomy
  • Version 1.4: 2023-12-13
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description