Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation
Resource
Proceedings of the National Academy of Sciences 102 (37): 13117-13122
Journal
Proceedings of the National Academy of Sciences
Pages
13117-13122
Date Issued
2005
Date
2005
Author(s)
Huang, Kai-Fa
Liu, Yi-Liang
Cheng, Wei-Ju
Ko, Tzu-Ping
Wang, Andrew H.-J.
Abstract
N-terminal pyroglutamate (pGlu) formation from its glutaminyl (or glutamyl) precursor is required in the maturation of numerous bioactive peptides. The aberrant formation of pGlu may be related to several pathological processes, such as osteoporosis and amyloidotic diseases. This N-terminal cyclization reaction, once thought to proceed spontaneously, is greatly facilitated by the enzyme glutaminyl cyclase (QC). To probe this important but poorly understood modification, we present here the structure of human QC in free form and bound to a substrate and three imidazole-derived inhibitors. The structure reveals an α/β scaffold akin to that of two-zinc exopeptidases but with several insertions and deletions, particularly in the active-site region. The relatively closed active site displays alternate conformations due to the different indole orientations of Trp-207, resulting in two substrate (glutamine t-butyl ester)-binding modes. The single zinc ion in the active site is coordinated to three conserved residues and one water molecule, which is replaced by an imidazole nitrogen upon binding of the inhibitors. Together with structural and kinetic analyses of several active-site-mutant enzymes, a catalysis mechanism of the formation of protein N-terminal pGlu is proposed. Our results provide a structural basis for the rational design of inhibitors against QC-associated disorders. ? 2005 by The National Academy of Sciences of the USA.
Subjects
Alzheimer's disease; Aminopeptidase; Crystallography; Intramolecular cyclization; Posttranslational modification
SDGs
Other Subjects
acyltransferase; exopeptidase; glutamine; glutaminyl cyclase; imidazole derivative; indole derivative; nitrogen; pyroglutamic acid; tryptophan; unclassified drug; water; zinc ion; alpha chain; Alzheimer disease; amino terminal sequence; amyloidosis; article; beta chain; catalysis; crystal structure; cyclization; enzyme active site; enzyme conformation; enzyme kinetics; enzyme structure; gene deletion; gene insertion; osteoporosis; priority journal; Aminoacyltransferases; Binding Sites; Catalysis; Crystallography, X-Ray; Enzyme Inhibitors; Humans; Imidazoles; Kinetics; Molecular Structure; Mutation; Protein Binding; Protein Structure, Secondary; Water; Zinc
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