RCSB PDB - 4C6V: Crystal structure of M. tuberculosis KasA in complex with TLM5 (Soak for 5 min)

 4C6V

Crystal structure of M. tuberculosis KasA in complex with TLM5 (Soak for 5 min)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.180 

Starting Model: experimental
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Ligand Structure Quality Assessment 

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This is version 1.4 of the entry. See complete history


Literature

Structural Basis for the Recognition of Mycolic Acid Precursors by Kasa, a Condensing Enzyme and Drug Target from Mycobacterium Tuberculosis

Schiebel, J.Kapilashrami, K.Fekete, A.Bommineni, G.R.Schaefer, C.M.Mueller, M.J.Tonge, P.J.Kisker, C.

(2013) J Biol Chem 288: 34190

  • DOI: https://doi.org/10.1074/jbc.M113.511436
  • Primary Citation of Related Structures:  
    4C6U, 4C6V, 4C6W, 4C6X, 4C6Z, 4C70, 4C71, 4C72, 4C73

  • PubMed Abstract: 

    The survival of Mycobacterium tuberculosis depends on mycolic acids, very long α-alkyl-β-hydroxy fatty acids comprising 60-90 carbon atoms. However, despite considerable efforts, little is known about how enzymes involved in mycolic acid biosynthesis recognize and bind their hydrophobic fatty acyl substrates. The condensing enzyme KasA is pivotal for the synthesis of very long (C38-42) fatty acids, the precursors of mycolic acids. To probe the mechanism of substrate and inhibitor recognition by KasA, we determined the structure of this protein in complex with a mycobacterial phospholipid and with several thiolactomycin derivatives that were designed as substrate analogs. Our structures provide consecutive snapshots along the reaction coordinate for the enzyme-catalyzed reaction and support an induced fit mechanism in which a wide cavity is established through the concerted opening of three gatekeeping residues and several α-helices. The stepwise characterization of the binding process provides mechanistic insights into the induced fit recognition in this system and serves as an excellent foundation for the development of high affinity KasA inhibitors.


  • Organizational Affiliation

    Rudolf Virchow Center for Experimental Biomedicine, Institute for Structural Biology, University of Wuerzburg, D-97080 Wuerzburg, Germany; Institute of Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, D-97074 Wuerzburg, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
3-OXOACYL-[ACYL-CARRIER-PROTEIN] SYNTHASE 1439Mycobacterium tuberculosis H37RvMutation(s): 0 
EC: 2.3.1.41
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
TLG PDBBind:  4C6V Kd: 2.56e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.180 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.23α = 90
b = 77.23β = 90
c = 146.851γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing

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 TLGClick on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-10-09
    Type: Initial release
  • Version 1.1: 2013-10-16
    Changes: Database references
  • Version 1.2: 2013-10-23
    Changes: Database references
  • Version 1.3: 2013-12-11
    Changes: Database references
  • Version 1.4: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description