8KCS
Cryo-EM structure of human gamma-secretase in complex with BMS906024
Summary for 8KCS
| Entry DOI | 10.2210/pdb8kcs/pdb |
| EMDB information | 37108 |
| Descriptor | Nicastrin, CHOLESTEROL, Presenilin-1, ... (10 entities in total) |
| Functional Keywords | intramembrane protease, gamma-secretase, gamma-secretase inhibitor, membrane protein, membrane protein-hydrolase complex |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 179048.95 |
| Authors | |
| Primary citation | Guo, X.,Li, H.,Lu, X.,Liu, H.,U, K.,Yan, C.,Lei, J.,Huang, J.,Zhou, R.,Shi, Y. Structural basis of human gamma-secretase inhibition by anticancer clinical compounds. Nat.Struct.Mol.Biol., 32:719-728, 2025 Cited by PubMed Abstract: 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. PubMed: 39653842DOI: 10.1038/s41594-024-01439-8 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.4 Å) |
Structure validation
Download full validation report
