2AFX

Crystal structure of human glutaminyl cyclase in complex with 1-benzylimidazole

2AFX の概要

• エントリーDOI: 10.2210/pdb2afx/pdb
• 関連するPDBエントリー: 2AFO 2AFS 2AFU 2AFW 2AFZ
• 分子名称: Glutaminyl-peptide cyclotransferase, ZINC ION, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: alpha-beta protein, metalloprotein, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted: Q16769
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 75754.14

構造登録者

Huang, K.F.,Liu, Y.L.,Cheng, W.J.,Ko, T.P.,Wang, A.H.J. (登録日: 2005-07-26, 公開日: 2005-08-23, 最終更新日: 2024-03-13)

主引用文献

Huang, K.F.,Liu, Y.L.,Cheng, W.J.,Ko, T.P.,Wang, A.H.
Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation
Proc.Natl.Acad.Sci.Usa, 102:13117-13122, 2005

PubMed 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 alpha/beta 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.

PubMed: 16135565
DOI: 10.1073/pnas.0504184102

実験手法

X-RAY DIFFRACTION (1.64 Å)