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Structure paper

TitleStructural basis of γ-secretase inhibition and modulation by small molecule drugs.
Journal, issue, pagesCell, Vol. 184, Issue 2, Page 521-533.e14, Year 2021
Publish dateJan 21, 2021
AuthorsGuanghui Yang / Rui Zhou / Xuefei Guo / Chuangye Yan / Jianlin Lei / Yigong Shi /
PubMed AbstractDevelopment 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.
External linksCell / PubMed:33373587
MethodsEM (single particle)
Resolution2.6 - 3.1 Å
Structure data

0944

6lqg

EMDB-0944, PDB-6lqg:
Human gamma-secretase in complex with small molecule Avagacestat
Method: EM (single particle) / Resolution: 3.1 Å

0957

6lr4

EMDB-0957, PDB-6lr4:
Molecular basis for inhibition of human gamma-secretase by small molecule
Method: EM (single particle) / Resolution: 3.0 Å

30312

7c9i

EMDB-30312, PDB-7c9i:
Human gamma-secretase in complex with small molecule L-685,458
Method: EM (single particle) / Resolution: 3.1 Å

30614

7d8x

EMDB-30614, PDB-7d8x:
CryoEM structure of human gamma-secretase in complex with E2012 and L685458
Method: EM (single particle) / Resolution: 2.6 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-EN9:
(2R)-2-[(4-chlorophenyl)sulfonyl-[[2-fluoranyl-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-tris(fluoranyl)pentanamide

ChemComp-PC1:
1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM / Phosphatidylcholine

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-ESF:
(2S)-2-hydroxy-3-methyl-N-[(2S)-1-[[(5S)-3-methyl-4-oxo-2,5-dihydro-1H-3-benzazepin-5-yl]amino]-1-oxopropan-2-yl]butanamide / Semagacestat

ChemComp-FTO:
~{tert}-butyl ~{N}-[(2~{S},3~{R},5~{R})-6-[[(2~{S})-1-[[(2~{S})-1-azanyl-1-oxidanylidene-3-phenyl-propan-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl]amino]-3-oxidanyl-6-oxidanylidene-1-phenyl-5-(phenylmethyl)hexan-2-yl]carbamate

ChemComp-GZR:
1-[(1S)-1-(4-fluorophenyl)ethyl]-3-[[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]methylidene]piperidin-2-one

ChemComp-PTY:
PHOSPHATIDYLETHANOLAMINE / phospholipid*YM / Phosphatidylethanolamine

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN/HYDROLASE / small molecule / MEMBRANE PROTEIN / MEMBRANE PROTEIN-HYDROLASE complex / Inhibitor / HYDROLASE / complex / modulator

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