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5FN4

Cryo-EM structure of gamma secretase in class 2 of the apo- state ensemble

Summary for 5FN4
Entry DOI10.2210/pdb5fn4/pdb
Related5FN2 5FN3 5FN5
EMDB information3239
DescriptorNicastrin, Presenilin-1, Gamma-secretase subunit APH-1A, ... (5 entities in total)
Functional Keywordshydrolase
Biological sourceHomo sapiens (Human)
More
Total number of polymer chains5
Total formula weight174048.04
Authors
Bai, X.C.,Rajendra, E.,Yang, G.H.,Shi, Y.G.,Scheres, S.H.W. (deposition date: 2015-11-10, release date: 2015-12-16, Last modification date: 2024-10-23)
Primary citationBai, X.C.,Rajendra, E.,Yang, G.,Shi, Y.,Scheres, S.H.
Sampling the conformational space of the catalytic subunit of human gamma-secretase.
Elife, 4:-, 2015
Cited by
PubMed Abstract: Human γ-secretase is an intra-membrane protease that cleaves many different substrates. Aberrant cleavage of Notch is implicated in cancer, while abnormalities in cutting amyloid precursor protein lead to Alzheimer's disease. Our previous cryo-EM structure of γ-secretase revealed considerable disorder in its catalytic subunit presenilin. Here, we describe an image classification procedure that characterizes molecular plasticity at the secondary structure level, and apply this method to identify three distinct conformations in our previous sample. In one of these conformations, an additional transmembrane helix is visible that cannot be attributed to the known components of γ-secretase. In addition, we present a γ-secretase structure in complex with the dipeptidic inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). Our results reveal how conformational mobility in the second and sixth transmembrane helices of presenilin is greatly reduced upon binding of DAPT or the additional helix, and form the basis for a new model of how substrate enters the transmembrane domain.
PubMed: 26623517
DOI: 10.7554/eLife.11182
PDB entries with the same primary citation
Experimental method
ELECTRON MICROSCOPY (4 Å)
Structure validation

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