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-Structure paper
タイトル | Structural basis of γ-secretase inhibition and modulation by small molecule drugs. |
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ジャーナル・号・ページ | Cell, Vol. 184, Issue 2, Page 521-533.e14, Year 2021 |
掲載日 | 2021年1月21日 |
著者 | Guanghui Yang / Rui Zhou / Xuefei Guo / Chuangye Yan / Jianlin Lei / Yigong Shi / |
PubMed 要旨 | 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 ...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. |
リンク | Cell / PubMed:33373587 |
手法 | EM (単粒子) |
解像度 | 2.6 - 3.1 Å |
構造データ | EMDB-0944, PDB-6lqg: EMDB-0957, PDB-6lr4: EMDB-30312, PDB-7c9i: EMDB-30614, PDB-7d8x: |
化合物 | ChemComp-NAG: ChemComp-EN9: ChemComp-PC1: ChemComp-CLR: ChemComp-ESF: ChemComp-FTO: ChemComp-GZR: ChemComp-PTY: |
由来 |
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キーワード | MEMBRANE PROTEIN/HYDROLASE / small molecule / MEMBRANE PROTEIN / MEMBRANE PROTEIN-HYDROLASE complex / Inhibitor / HYDROLASE / complex / modulator |