6YI1

Crystal structure of human glutaminyl cyclase in complex with Glu(gamma-hydrazide)-Phe-Ala

6YI1 の概要

• エントリーDOI: 10.2210/pdb6yi1/pdb
• 分子名称: Glutaminyl-peptide cyclotransferase, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, Glu(gamma-hydrazide)-Phe-Ala, ... (11 entities in total)
• 機能のキーワード: alpha-beta protein, metalloprotein, transferase, intermediate
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 80302.53

構造登録者

Kupski, O.,Sautner, V.,Tittmann, K. (登録日: 2020-03-31, 公開日: 2020-07-01, 最終更新日: 2024-07-10)

主引用文献

Kupski, O.,Funk, L.M.,Sautner, V.,Seifert, F.,Worbs, B.,Ramsbeck, D.,Meyer, F.,Diederichsen, U.,Buchholz, M.,Schilling, S.,Demuth, H.U.,Tittmann, K.
Hydrazides Are Potent Transition-State Analogues for Glutaminyl Cyclase Implicated in the Pathogenesis of Alzheimer's Disease.
Biochemistry, 59:2585-2591, 2020

PubMed Abstract: Amyloidogenic plaques are hallmarks of Alzheimer's disease (AD) and typically consist of high percentages of modified Aβ peptides bearing N-terminally cyclized glutamate residues. The human zinc(II) enzyme glutaminyl cyclase (QC) was shown in vivo to catalyze the cyclization of N-terminal glutamates of Aβ peptides in a pathophysiological side reaction establishing QC as a druggable target for therapeutic treatment of AD. Here, we report crystallographic snapshots of human QC catalysis acting on the neurohormone neurotensin that delineate the stereochemical course of catalysis and suggest that hydrazides could mimic the transition state of peptide cyclization and deamidation. This hypothesis is validated by a sparse-matrix inhibitor screening campaign that identifies hydrazides as the most potent metal-binding group compared to classic Zn binders. The structural basis of hydrazide inhibition is illuminated by X-ray structure analysis of human QC in complex with a hydrazide-bearing peptide inhibitor and reveals a pentacoordinated Zn complex. Our findings inform novel strategies in the design of potent and highly selective QC inhibitors by employing hydrazides as the metal-binding warhead.

PubMed: 32551535
DOI: 10.1021/acs.biochem.0c00337

実験手法

X-RAY DIFFRACTION (1.92 Å)