5DVP

Crystal structure of Mycobacterium tuberculosis L,D-transpeptidase 2 with Doripenem adduct


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.18 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.176 

Starting Model: experimental
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Ligand Structure Quality Assessment 

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This is version 1.6 of the entry. See complete history


Literature

Non-classical transpeptidases yield insight into new antibacterials.

Kumar, P.Kaushik, A.Lloyd, E.P.Li, S.G.Mattoo, R.Ammerman, N.C.Bell, D.T.Perryman, A.L.Zandi, T.A.Ekins, S.Ginell, S.L.Townsend, C.A.Freundlich, J.S.Lamichhane, G.

(2017) Nat Chem Biol 13: 54-61

  • DOI: https://doi.org/10.1038/nchembio.2237
  • Primary Citation of Related Structures:  
    5DU7, 5DUJ, 5DVP, 5DZJ, 5DZP, 5E1G, 5E1I, 5E51, 5E5L, 5K69

  • PubMed Abstract: 

    Bacterial survival requires an intact peptidoglycan layer, a three-dimensional exoskeleton that encapsulates the cytoplasmic membrane. Historically, the final steps of peptidoglycan synthesis are known to be carried out by D,D-transpeptidases, enzymes that are inhibited by the β-lactams, which constitute >50% of all antibacterials in clinical use. Here, we show that the carbapenem subclass of β-lactams are distinctly effective not only because they inhibit D,D-transpeptidases and are poor substrates for β-lactamases, but primarily because they also inhibit non-classical transpeptidases, namely the L,D-transpeptidases, which generate the majority of linkages in the peptidoglycan of mycobacteria. We have characterized the molecular mechanisms responsible for inhibition of L,D-transpeptidases of Mycobacterium tuberculosis and a range of bacteria including ESKAPE pathogens, and used this information to design, synthesize and test simplified carbapenems with potent antibacterial activity.


  • Organizational Affiliation

    Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
L,D-transpeptidase 2
A, B
350Mycobacterium tuberculosis H37RvMutation(s): 0 
Gene Names: ldtBlppSRv2518cRVBD_2518cP425_02624
EC: 2.3.2
UniProt
Find proteins for I6Y9J2 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore I6Y9J2 
Go to UniProtKB:  I6Y9J2
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupI6Y9J2
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.18 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.176 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 60.866α = 90
b = 93.062β = 92.91
c = 75.213γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-3000data reduction
HKL-3000data scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted DRWClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/Office of the DirectorUnited States1DP2OD008459-01

Revision History  (Full details and data files)

  • Version 1.0: 2016-09-28
    Type: Initial release
  • Version 1.1: 2016-11-09
    Changes: Database references
  • Version 1.2: 2016-11-23
    Changes: Database references
  • Version 1.3: 2016-12-28
    Changes: Database references
  • Version 1.4: 2017-09-20
    Changes: Author supporting evidence
  • Version 1.5: 2023-09-27
    Changes: Data collection, Database references, Refinement description
  • Version 1.6: 2024-10-09
    Changes: Structure summary