5FN3: Cryo-em Structure Of Gamma Secretase In Class 1 Of The Apo- State Ensemble

Human gamma-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 gamma-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 gamma-secretase. In addition, we present a gamma-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.
PDB ID: 5FN3Download
MMDB ID: 134934
PDB Deposition Date: 2015/11/10
Updated in MMDB: 2016/12
Experimental Method:
electron microscopy
Resolution: 4.1  Å
Source Organism:
Similar Structures:
Biological Unit for 5FN3: pentameric; determined by author and by software (PISA)
Molecular Components in 5FN3
Label Count Molecule
Proteins (5 molecules)
Nicastrin(Gene symbol: NCSTN)
Molecule annotation
Presenilin-1(Gene symbol: PSEN1)
Molecule annotation
Gamma-secretase Subunit Aph-1a(Gene symbol: APH1A)
Molecule annotation
Gamma-secretase Subunit Pen-2(Gene symbol: PSENEN)
Molecule annotation
Poly ALA Chain
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB