2H9I

Mycobacterium tuberculosis InhA bound with ETH-NAD adduct


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.233 
  • R-Value Observed: 0.237 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Mechanism of thioamide drug action against tuberculosis and leprosy.

Wang, F.Langley, R.Gulten, G.Dover, L.G.Besra, G.S.Jacobs, W.R.Sacchettini, J.C.

(2007) J Exp Med 204: 73-78

  • DOI: https://doi.org/10.1084/jem.20062100
  • Primary Citation of Related Structures:  
    2H9I, 2NTJ, 2NTV

  • PubMed Abstract: 

    Thioamide drugs, ethionamide (ETH) and prothionamide (PTH), are clinically effective in the treatment of Mycobacterium tuberculosis, M. leprae, and M. avium complex infections. Although generally considered second-line drugs for tuberculosis, their use has increased considerably as the number of multidrug resistant and extensively drug resistant tuberculosis cases continues to rise. Despite the widespread use of thioamide drugs to treat tuberculosis and leprosy, their precise mechanisms of action remain unknown. Using a cell-based activation method, we now have definitive evidence that both thioamides form covalent adducts with nicotinamide adenine dinucleotide (NAD) and that these adducts are tight-binding inhibitors of M. tuberculosis and M. leprae InhA. The crystal structures of the inhibited M. leprae and M. tuberculosis InhA complexes provide the molecular details of target-drug interactions. The purified ETH-NAD and PTH-NAD adducts both showed nanomolar Kis against M. tuberculosis and M. leprae InhA. Knowledge of the precise structures and mechanisms of action of these drugs provides insights into designing new drugs that can overcome drug resistance.


  • Organizational Affiliation

    Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Enoyl-[acyl-carrier-protein] reductase [NADH]268Mycobacterium tuberculosisMutation(s): 1 
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
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
EAD
Query on EAD

Download Ideal Coordinates CCD File 
B [auth A]{(2R,3S,4R,5R)-5-[(4S)-3-(AMINOCARBONYL)-4-(2-ETHYLISONICOTINOYL)PYRIDIN-1(4H)-YL]-3,4-DIHYDROXYTETRAHYDROFURAN-2-YL}METHYL [(2R,3S,4R,5R)-5-(6-AMINO-9H-PURIN-9-YL)-3,4-DIHYDROXYTETRAHYDROFURAN-2-YL]METHYL DIHYDROGEN DIPHOSPHATE
C29 H36 N8 O15 P2
KVEIKWLOSUPDGF-OYBINNFYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.233 
  • R-Value Observed: 0.237 
  • Space Group: P 62 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 97.934α = 90
b = 97.934β = 90
c = 140.42γ = 120
Software Package:
Software NamePurpose
CNSrefinement
PDB_EXTRACTdata extraction
ADSCdata collection
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: 2007-01-30
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Derived calculations, Version format compliance
  • Version 1.3: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.4: 2023-08-30
    Changes: Data collection, Refinement description