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

Research output: Contribution to journalArticlepeer-review

80 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)13117-13122
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number37
DOIs
Publication statusPublished - Sep 13 2005
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Aminopeptidase
  • Crystallography
  • Intramolecular cyclization
  • Posttranslational modification

ASJC Scopus subject areas

  • General

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