Cofactor-induced conformational rearrangements establish a catalytically competent active site and a proton relay conduit in FabG

Structure. 2004 Mar;12(3):417-28. doi: 10.1016/j.str.2004.02.008.


beta-Ketoacyl-acyl carrier protein reductase (FabG) is a key component in the type II fatty acid synthase system. The structures of Escherichia coli FabG and the FabG[Y151F] mutant in binary complexes with NADP(H) reveal that mechanistically important conformational changes accompany cofactor binding. The active site Ser-Tyr-Lys triad is repositioned into a catalytically competent constellation, and a hydrogen bonded network consisting of ribose hydroxyls, the Ser-Tyr-Lys triad, and four water molecules creates a proton wire to replenish the tyrosine proton donated during catalysis. Also, a disordered loop in FabG forms a substructure in the complex that shapes the entrance to the active site. A key observation is that the nicotinamide portion of the cofactor is disordered in the FabG[Y151F].NADP(H) complex, and Tyr151 appears to be necessary for high-affinity cofactor binding. Biochemical data confirm that FabG[Y151F] is defective in NADPH binding. Finally, structural changes consistent with the observed negative cooperativity of FabG are described.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alcohol Oxidoreductases / chemistry
  • Alcohol Oxidoreductases / metabolism*
  • Binding Sites
  • Calcium / metabolism
  • Catalytic Domain*
  • Crystallography, X-Ray
  • Escherichia coli / enzymology
  • NADP / metabolism*
  • Protein Binding
  • Protein Conformation
  • Protons*


  • Protons
  • NADP
  • Alcohol Oxidoreductases
  • acetoacetyl-CoA reductase
  • Calcium

Associated data

  • PDB/1Q7B
  • PDB/1Q7C