1LXC

Crystal Structure of E. Coli Enoyl Reductase-NAD+ with a Bound Acrylamide Inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.199 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Discovery of aminopyridine-based inhibitors of bacterial enoyl-ACP reductase (FabI).

Miller, W.H.Seefeld, M.A.Newlander, K.A.Uzinskas, I.N.Burgess, W.J.Heerding, D.A.Yuan, C.C.Head, M.S.Payne, D.J.Rittenhouse, S.F.Moore, T.D.Pearson, S.C.Berry, V.DeWolf Jr., W.E.Keller, P.M.Polizzi, B.J.Qiu, X.Janson, C.A.Huffman, W.F.

(2002) J Med Chem 45: 3246-3256

  • DOI: https://doi.org/10.1021/jm020050+
  • Primary Citation of Related Structures:  
    1LX6, 1LXC

  • PubMed Abstract: 

    Bacterial enoyl-ACP reductase (FabI) catalyzes the final step in each cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. Our efforts to identify potent, selective FabI inhibitors began with screening of the GlaxoSmithKline proprietary compound collection, which identified several small-molecule inhibitors of Staphylococcus aureus FabI. Through a combination of iterative medicinal chemistry and X-ray crystal structure based design, one of these leads was developed into the novel aminopyridine derivative 9, a low micromolar inhibitor of FabI from S. aureus (IC(50) = 2.4 microM) and Haemophilus influenzae (IC(50) = 4.2 microM). Compound 9 has good in vitro antibacterial activity against several organisms, including S. aureus (MIC = 0.5 microg/mL), and is effective in vivo in a S. aureus groin abscess infection model in rats. Through FabI overexpressor and macromolecular synthesis studies, the mode of action of 9 has been confirmed to be inhibition of fatty acid biosynthesis via inhibition of FabI. Taken together, these results support FabI as a valid antibacterial target and demonstrate the potential of small-molecule FabI inhibitors for the treatment of bacterial infections.


  • Organizational Affiliation

    GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, P.O. Box 5089, Collegeville, PA 19426, USA. william_h_miller@gsk.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADH]
A, B
262Escherichia coliMutation(s): 0 
EC: 1.3.1.9
UniProt
Find proteins for P0AEK4 (Escherichia coli (strain K12))
Explore P0AEK4 
Go to UniProtKB:  P0AEK4
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP0AEK4
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 
C [auth A],
E [auth B]
NICOTINAMIDE-ADENINE-DINUCLEOTIDE
C21 H27 N7 O14 P2
BAWFJGJZGIEFAR-NNYOXOHSSA-N
AYM
Query on AYM

Download Ideal Coordinates CCD File 
D [auth A],
F [auth B]
3-(6-AMINOPYRIDIN-3-YL)-N-METHYL-N-[(1-METHYL-1H-INDOL-2-YL)METHYL]ACRYLAMIDE
C19 H20 N4 O
AKFPMLBVLWZSQX-CSKARUKUSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
AYM Binding MOAD:  1LXC IC50: 370 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.199 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 79.58α = 90
b = 79.58β = 90
c = 326.17γ = 120
Software Package:
Software NamePurpose
CNXrefinement
DENZOdata reduction
SCALEPACKdata scaling
CNXphasing

Structure Validation

View Full Validation Report



Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2002-09-04
    Type: Initial release
  • Version 1.1: 2008-04-28
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Derived calculations, Version format compliance
  • Version 1.3: 2024-02-14
    Changes: Data collection, Database references, Derived calculations, Refinement description