8KCP

Cryo-EM structure of human gamma-secretase in complex with Crenigacestat

8KCP の概要

• エントリーDOI: 10.2210/pdb8kcp/pdb
• EMDBエントリー: 37107
• 分子名称: Nicastrin, CHOLESTEROL, Presenilin-1, ... (10 entities in total)
• 機能のキーワード: intramembrane protease, gamma-secretase, gamma-secretase inhibitor, membrane protein, membrane protein-hydrolase complex
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 178956.89

構造登録者

Guo, X.,Li, H.,Kai, U.,Yan, C.,Lei, J.,Zhou, R.,Shi, Y. (登録日: 2023-08-08, 公開日: 2024-08-14, 最終更新日: 2025-04-30)

主引用文献

Guo, X.,Li, H.,Lu, X.,Liu, H.,U, K.,Yan, C.,Lei, J.,Huang, J.,Zhou, R.,Shi, Y.
Structural basis of human gamma-secretase inhibition by anticancer clinical compounds.
Nat.Struct.Mol.Biol., 32:719-728, 2025

PubMed Abstract: Aberrant activation of Notch signaling, mediated by the Notch intracellular domain (NICD), is linked to certain types of cancer. The NICD is released through γ-secretase-mediated cleavage of the Notch receptor. Therefore, development of a γ-secretase inhibitor (GSI) represents an anticancer strategy. Here we report the cryo-electron microscopy structures of human γ-secretase bound individually to five clinically tested GSIs (RO4929097, crenigacestat, BMS906024, nirogacestat and MK-0752) at overall resolutions of 2.4-3.0 Å. Three of the five GSIs are in active anticancer clinical trials, while nirogacestat was recently approved. Each of these GSIs similarly occupies the substrate-binding site of presenilin 1 but shows characteristic differences in detailed recognition pattern. The size and shape of the binding pocket are induced by the bound GSI. Analysis of these structural features suggest strategies for modification of the GSI with improved inhibition potency.

PubMed: 39653842
DOI: 10.1038/s41594-024-01439-8

実験手法

ELECTRON MICROSCOPY (3 Å)