6LR4

Molecular basis for inhibition of human gamma-secretase by small molecule

6LR4 の概要

• エントリーDOI: 10.2210/pdb6lr4/pdb
• EMDBエントリー: 0944 0957
• 分子名称: Nicastrin, CHOLESTEROL, Presenilin-1, ... (10 entities in total)
• 機能のキーワード: inhibitor, membrane protein
• 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: 184175.49

構造登録者

Yang, G.,Zhou, R.,Guo, X.,Lei, J.,Shi, Y. (登録日: 2020-01-15, 公開日: 2021-01-27, 最終更新日: 2025-07-02)

主引用文献

Yang, G.,Zhou, R.,Guo, X.,Yan, C.,Lei, J.,Shi, Y.
Structural basis of gamma-secretase inhibition and modulation by small molecule drugs.
Cell, 184:521-533.e14, 2021

PubMed Abstract: Development of γ-secretase inhibitors (GSIs) and modulators (GSMs) represents an attractive therapeutic opportunity for Alzheimer's disease (AD) and cancers. However, how these GSIs and GSMs target γ-secretase has remained largely unknown. Here, we report the cryoelectron microscopy (cryo-EM) structures of human γ-secretase bound individually to two GSI clinical candidates, Semagacestat and Avagacestat, a transition state analog GSI L685,458, and a classic GSM E2012, at overall resolutions of 2.6-3.1 Å. Remarkably, each of the GSIs occupies the same general location on presenilin 1 (PS1) that accommodates the β strand from amyloid precursor protein or Notch, interfering with substrate recruitment. L685,458 directly coordinates the two catalytic aspartate residues of PS1. E2012 binds to an allosteric site of γ-secretase on the extracellular side, potentially explaining its modulating activity. Structural analysis reveals a set of shared themes and variations for inhibitor and modulator recognition that will guide development of the next-generation substrate-selective inhibitors.

PubMed: 33373587
DOI: 10.1016/j.cell.2020.11.049

実験手法

ELECTRON MICROSCOPY (3 Å)