Abstract
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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acid Anhydride Hydrolases*
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Adenosine / metabolism
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Adenosine Diphosphate / analogs & derivatives
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Adenosine Diphosphate / metabolism
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Adenosine Monophosphate / metabolism
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Adenosine Triphosphate / metabolism
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Binding Sites
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Catalysis
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Crystallography, X-Ray
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Dimerization
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Dinucleoside Phosphates / metabolism
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Hydrogen Bonding
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Neoplasm Proteins*
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Nerve Tissue Proteins / chemistry
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Nerve Tissue Proteins / metabolism*
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Protein Structure, Secondary
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Proteins / chemistry
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Proteins / metabolism*
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Structure-Activity Relationship
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Substrate Specificity
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Tungsten Compounds / metabolism
Substances
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Dinucleoside Phosphates
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Neoplasm Proteins
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Nerve Tissue Proteins
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Proteins
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Tungsten Compounds
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fragile histidine triad protein
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alpha,beta-methyleneadenosine 5'-diphosphate
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Adenosine Monophosphate
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Adenosine Diphosphate
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sodium tungstate(VI)
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Adenosine Triphosphate
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Acid Anhydride Hydrolases
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Adenosine