3PB8

Crystal structure of the catalytic domain of human Golgi-resident glutaminyl cyclase in complex with N-acetylhistamine

3PB8 の概要

• エントリーDOI: 10.2210/pdb3pb8/pdb
• 関連するPDBエントリー: 3PB4 3PB6 3PB7 3PB9 3PBB 3PBE
• 分子名称: Glutaminyl-peptide cyclotransferase-like protein, N-[2-(1H-IMIDAZOL-4-YL)ETHYL]ACETAMIDE, ZINC ION, ... (4 entities in total)
• 機能のキーワード: alpha/beta protein, alpha/beta-mixed fold, glutaminyl cyclase, golgi membrane, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Golgi apparatus membrane; Single-pass type I membrane protein: Q9NXS2
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37287.32

構造登録者

Huang, K.F.,Liaw, S.S.,Huang, W.L.,Chia, C.Y.,Lo, Y.C.,Chen, Y.L.,Wang, A.H.J. (登録日: 2010-10-20, 公開日: 2011-02-02, 最終更新日: 2023-11-01)

主引用文献

Huang, K.F.,Liaw, S.S.,Huang, W.L.,Chia, C.Y.,Lo, Y.C.,Chen, Y.L.,Wang, A.H.J.
Structures of human Golgi-resident glutaminyl cyclase and its complexes with inhibitors reveal a large loop movement upon inhibitor binding
J.Biol.Chem., 286:12439-12449, 2011

PubMed Abstract: Aberrant pyroglutamate formation at the N terminus of certain peptides and proteins, catalyzed by glutaminyl cyclases (QCs), is linked to some pathological conditions, such as Alzheimer disease. Recently, a glutaminyl cyclase (QC) inhibitor, PBD150, was shown to be able to reduce the deposition of pyroglutamate-modified amyloid-β peptides in brain of transgenic mouse models of Alzheimer disease, leading to a significant improvement of learning and memory in those transgenic animals. Here, we report the 1.05-1.40 Å resolution structures, solved by the sulfur single-wavelength anomalous dispersion phasing method, of the Golgi-luminal catalytic domain of the recently identified Golgi-resident QC (gQC) and its complex with PBD150. We also describe the high-resolution structures of secretory QC (sQC)-PBD150 complex and two other gQC-inhibitor complexes. gQC structure has a scaffold similar to that of sQC but with a relatively wider and negatively charged active site, suggesting a distinct substrate specificity from sQC. Upon binding to PBD150, a large loop movement in gQC allows the inhibitor to be tightly held in its active site primarily by hydrophobic interactions. Further comparisons of the inhibitor-bound structures revealed distinct interactions of the inhibitors with gQC and sQC, which are consistent with the results from our inhibitor assays reported here. Because gQC and sQC may play different biological roles in vivo, the different inhibitor binding modes allow the design of specific inhibitors toward gQC and sQC.

PubMed: 21288892
DOI: 10.1074/jbc.M110.208595

実験手法

X-RAY DIFFRACTION (1.13 Å)