6LR4

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

Summary for 6LR4

• Entry DOI: 10.2210/pdb6lr4/pdb
• EMDB information: 0944 0957
• Descriptor: Nicastrin, CHOLESTEROL, Presenilin-1, ... (10 entities in total)
• Functional Keywords: inhibitor, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 184175.49

Authors

Yang, G.,Zhou, R.,Guo, X.,Lei, J.,Shi, Y. (deposition date: 2020-01-15, release date: 2021-01-27, Last modification date: 2025-07-02)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3 Å)