Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation

Kai Fa Huang, Yi Liang Liu, Wei Ju Cheng, Tzu Ping Ko, Andrew H.J. Wang

研究成果: 雜誌貢獻文章同行評審

83 引文 斯高帕斯(Scopus)

摘要

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.

原文英語
頁(從 - 到)13117-13122
頁數6
期刊Proceedings of the National Academy of Sciences of the United States of America
102
發行號37
DOIs
出版狀態已發佈 - 9月 13 2005
對外發佈

ASJC Scopus subject areas

  • 多學科

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