2NSD

Enoyl acyl carrier protein reductase InhA in complex with N-(4-methylbenzoyl)-4-benzylpiperidine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.236 
  • R-Value Observed: 0.236 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides.

He, X.Alian, A.Ortiz de Montellano, P.R.

(2007) Bioorg Med Chem 15: 6649-6658

  • DOI: https://doi.org/10.1016/j.bmc.2007.08.013
  • Primary Citation of Related Structures:  
    2NSD

  • PubMed Abstract: 

    InhA, the enoyl acyl carrier protein reductase (ENR) from Mycobacterium tuberculosis, is one of the key enzymes involved in the type II fatty acid biosynthesis pathway of M. tuberculosis. We report here the discovery, through high-throughput screening, of a series of arylamides as a novel class of potent InhA inhibitors. These direct InhA inhibitors require no mycobacterial enzymatic activation and thus circumvent the resistance mechanism to antitubercular prodrugs such as INH and ETA that is most commonly observed in drug-resistant clinical isolates. The crystal structure of InhA complexed with one representative inhibitor reveals the binding mode of the inhibitor within the InhA active site. Further optimization through a microtiter synthesis strategy followed by in situ activity screening led to the discovery of a potent InhA inhibitor with in vitro IC(50)=90 nM, representing a 34-fold potency improvement over the lead compound.


  • Organizational Affiliation

    Applied Technology Group, Incyte Corporation, Experimental Station, Wilmington, DE 19880, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Enoyl-[acyl-carrier-protein] reductase
A, B
269Mycobacterium tuberculosis H37RvMutation(s): 0 
Gene Names: inhA
EC: 1.3.1.9
UniProt
Find proteins for P9WGR1 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WGR1 
Go to UniProtKB:  P9WGR1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WGR1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
4PI BindingDB:  2NSD IC50: 5160 (nM) from 1 assay(s)
Binding MOAD:  2NSD IC50: 5160 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.236 
  • R-Value Observed: 0.236 
  • Space Group: I 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 91.263α = 90
b = 91.327β = 90
c = 184.259γ = 90
Software Package:
Software NamePurpose
CNSrefinement
ADSCdata collection
HKL-2000data reduction
HKL-2000data scaling
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-09-18
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description