Structure-based analysis of catalysis and substrate definition in the HIT protein family

Science. 1997 Oct 10;278(5336):286-90. doi: 10.1126/science.278.5336.286.


The histidine triad (HIT) protein family is among the most ubiquitous and highly conserved in nature, but a biological activity has not yet been identified for any member of the HIT family. Fragile histidine triad protein (FHIT) and protein kinase C interacting protein (PKCI) were used in a structure-based approach to elucidate characteristics of in vivo ligands and reactions. Crystallographic structures of apo, substrate analog, pentacovalent transition-state analog, and product states of both enzymes reveal a catalytic mechanism and define substrate characteristics required for catalysis, thus unifying the HIT family as nucleotidyl hydrolases, transferases, or both. The approach described here may be useful in identifying structure-function relations between protein families identified through genomics.

Publication types

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

MeSH terms

  • Acid Anhydride Hydrolases*
  • Adenosine / metabolism
  • Adenosine Diphosphate / analogs & derivatives
  • Adenosine Diphosphate / metabolism
  • Adenosine Monophosphate / metabolism
  • Adenosine Triphosphate / metabolism
  • Binding Sites
  • Catalysis
  • Crystallography, X-Ray
  • Dimerization
  • Dinucleoside Phosphates / metabolism
  • Hydrogen Bonding
  • Neoplasm Proteins*
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / metabolism*
  • Protein Structure, Secondary
  • Proteins / chemistry
  • Proteins / metabolism*
  • Structure-Activity Relationship
  • Substrate Specificity
  • Tungsten Compounds / metabolism


  • Dinucleoside Phosphates
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • Proteins
  • Tungsten Compounds
  • fragile histidine triad protein
  • alpha,beta-methyleneadenosine 5'-diphosphate
  • Adenosine Monophosphate
  • Adenosine Diphosphate
  • sodium tungstate(VI)
  • Adenosine Triphosphate
  • Acid Anhydride Hydrolases
  • Adenosine