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Structure paper

TitleStructural basis of human γ-secretase inhibition by anticancer clinical compounds.
Journal, issue, pagesNat Struct Mol Biol, Vol. 32, Issue 4, Page 719-728, Year 2025
Publish dateDec 9, 2024
AuthorsXuefei Guo / Haotian Li / Xiaoli Lu / Hao Liu / Kaicheng U / Chuangye Yan / Jianlin Lei / Jing Huang / Rui Zhou / Yigong Shi /
PubMed AbstractAberrant 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 ...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.
External linksNat Struct Mol Biol / PubMed:39653842
MethodsEM (single particle)
Resolution2.4 - 3.0 Å
Structure data

37106

8kco

EMDB-37106, PDB-8kco:
Cryo-EM structure of human gamma-secretase in complex with RO4929097
Method: EM (single particle) / Resolution: 2.8 Å

37107

8kcp

EMDB-37107, PDB-8kcp:
Cryo-EM structure of human gamma-secretase in complex with Crenigacestat
Method: EM (single particle) / Resolution: 3.0 Å

37108

8kcs

EMDB-37108, PDB-8kcs:
Cryo-EM structure of human gamma-secretase in complex with BMS906024
Method: EM (single particle) / Resolution: 2.4 Å

37109

8kct

EMDB-37109, PDB-8kct:
Cryo-EM structure of human gamma-secretase in complex with Nirogacestat
Method: EM (single particle) / Resolution: 2.6 Å

37110

8kcu

EMDB-37110, PDB-8kcu:
Cryo-EM structure of human gamma-secretase in complex with MK-0752
Method: EM (single particle) / Resolution: 2.7 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose


ChemComp, No image

ChemComp-N60:
Unknown entry

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

ChemComp-CLR:
CHOLESTEROL


ChemComp, No image

ChemComp-N9C:
Unknown entry


ChemComp, No image

ChemComp-Q70:
Unknown entry


ChemComp, No image

ChemComp-O6U:
Unknown entry


ChemComp, No image

ChemComp-OL9:
Unknown entry

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Intramembrane protease / gamma-secretase / gamma-secretase inhibitor / MEMBRANE PROTEIN-HYDROLASE complex

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