6LQG
Human gamma-secretase in complex with small molecule Avagacestat
Summary for 6LQG
| Entry DOI | 10.2210/pdb6lqg/pdb |
| EMDB information | 0944 |
| Descriptor | Nicastrin, CHOLESTEROL, Presenilin-1, ... (10 entities in total) |
| Functional Keywords | small molecule, membrane protein, membrane protein-hydrolase complex, membrane protein/hydrolase |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 184334.94 |
| Authors | |
| 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 Cited by 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: 33373587DOI: 10.1016/j.cell.2020.11.049 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.1 Å) |
Structure validation
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