4TZT

CRYSTAL STRUCTURE OF MYCOBACTERIUM TUBERCULOSIS ENOYL REDUCTASE (INHA) COMPLEXED WITH N-(3-CHLORO-2-METHYLPHENYL)-1-CYCLOHEXYL- 5-OXOPYRROLIDINE-3-CARBOXAMIDE


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.86 Å
  • R-Value Free: 0.168 
  • R-Value Work: 0.140 
  • R-Value Observed: 0.141 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis

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

(2006) J Med Chem : 6308-6323

  • DOI: https://doi.org/10.1021/jm060715y
  • Primary Citation of Related Structures:  
    4TRJ, 4TZK, 4TZT, 4U0J, 4U0K

  • PubMed Abstract: 

    In view of the worldwide spread of multidrug resistance of Mycobacterium tuberculosis, there is an urgent need to discover antituberculosis agent with novel structures. InhA, the enoyl acyl carrier protein reductase (ENR) from M. tuberculosis, is one of the key enzymes involved in the mycobacterial fatty acid elongation cycle and has been validated as an effective antimicrobial target. We report here the discovery, through high-throughput screening, of a series of pyrrolidine carboxamides as a novel class of potent InhA inhibitors. Crystal structures of InhA complexed with three inhibitors have been used to elucidate the inhibitor binding mode. The potency of the lead compound was improved over 160-fold by subsequent optimization through iterative microtiter library synthesis followed by in situ activity screening without purification. Resolution of racemic mixtures of several inhibitors indicate that only one enantiomer is active as an inhibitor of InhA.


  • Organizational Affiliation

    Department of Pharmaceutical Chemistry, University of California, 600 16 Street, San Francisco, California 94158-2517, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Enoyl-[acyl-carrier-protein] reductase [NADH]269Mycobacterium tuberculosis H37RvMutation(s): 0 
Gene Names: inhARv1484MTCY277.05
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
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAD
Query on NAD

Download Ideal Coordinates CCD File 
B [auth A]NICOTINAMIDE-ADENINE-DINUCLEOTIDE
C21 H27 N7 O14 P2
BAWFJGJZGIEFAR-NNYOXOHSSA-N
468
Query on 468

Download Ideal Coordinates CCD File 
C [auth A](3S)-N-(3-CHLORO-2-METHYLPHENYL)-1-CYCLOHEXYL-5-OXOPYRROLIDINE-3-CARBOXAMIDE
C18 H23 Cl N2 O2
NJNMAZNXKKBTPS-ZDUSSCGKSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
468 Binding MOAD:  4TZT IC50: 2.31e+4 (nM) from 1 assay(s)
BindingDB:  4TZT IC50: min: 2.31e+4, max: 2.31e+4 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.86 Å
  • R-Value Free: 0.168 
  • R-Value Work: 0.140 
  • R-Value Observed: 0.141 
  • Space Group: P 62 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 97.782α = 90
b = 97.782β = 90
c = 141.125γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
Cootmodel building
CNSphasing
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM56531

Revision History  (Full details and data files)

  • Version 1.0: 2014-08-20
    Type: Initial release
  • Version 1.1: 2017-09-20
    Changes: Advisory, Author supporting evidence, Derived calculations, Other, Refinement description, Source and taxonomy
  • Version 1.2: 2019-12-25
    Changes: Author supporting evidence
  • Version 1.3: 2023-12-27
    Changes: Data collection, Database references, Refinement description