A protein catalytic framework with an N-terminal nucleophile is capable of self-activation

THE crystal structures of three amidohydrolases have been determined recently 1–3 : glutamine PRPP amidotransferase (GAT), penicillin acylase, and the proteasome. These enzymes use the side chain of the amino-terminal residue, incorporated in a β-sheet, as the nucleophile in the catalytic attack at...

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Bibliographic Details
Published in:Nature (London) 1995-11, Vol.378 (6555), p.416-419
Main Authors: Brannigan, James A, Dodson, Guy, Duggleby, Helen J, Moody, Peter C. E, Smith, Janet L, Tomchick, Diana R, Murzin, Alexey G
Format: Article
Language:English
Subjects:
Amidophosphoribosyltransferase - chemistry
Amidophosphoribosyltransferase - metabolism
Amino acids
Analytical, structural and metabolic biochemistry
Binding Sites
Biochemistry
Biological and medical sciences
Carbonyl compounds
Catalysis
Crystallography, X-Ray
Cysteine Endopeptidases - chemistry
Cysteine Endopeptidases - metabolism
Enzyme Activation
Enzymes
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
Humanities and Social Sciences
letter
Miscellaneous
multidisciplinary
Multienzyme Complexes - chemistry
Multienzyme Complexes - metabolism
Penicillin Amidase - chemistry
Penicillin Amidase - metabolism
Proteasome Endopeptidase Complex
Protein Folding
Protein Processing, Post-Translational
Protein Structure, Secondary
Science
Structure-Activity Relationship
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Summary:THE crystal structures of three amidohydrolases have been determined recently 1–3 : glutamine PRPP amidotransferase (GAT), penicillin acylase, and the proteasome. These enzymes use the side chain of the amino-terminal residue, incorporated in a β-sheet, as the nucleophile in the catalytic attack at the carbonyl carbon. The nucleophile is cysteine in GAT, serine in penicillin acylase, and threonine in the proteasome. Here we show that all three enzymes share an unusual fold in which the nucleophile and other catalytic groups occupy equivalent sites. This fold provides both the capacity for nucleophilic attack and the possibility of autocatalytic processing. We suggest the name Ntn (N-terminal nucleophile) hydrolases for this structural superfamily of enzymes which appear to be evolutionarily related but which have diverged beyond any recog-nizable sequence similarity.
ISSN:0028-0836
1476-4687
DOI:10.1038/378416a0