5fn2 | pdb_00005fn2
Cryo-EM structure of gamma secretase in complex with a drug DAPT
Structural highlights
DiseaseNICA_HUMAN Hidradenitis suppurativa. The disease is caused by mutations affecting the gene represented in this entry. FunctionNICA_HUMAN Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). It probably represents a stabilizing cofactor required for the assembly of the gamma-secretase complex. Publication Abstract from PubMedHuman gamma-Secretase is an intra-membrane protease that cleaves many 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 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. Sampling the conformational space of the catalytic subunit of human gamma-secretase.,Bai XC, Rajendra E, Yang G, Shi Y, Scheres SH Elife. 2015 Dec 1;4. pii: e11182. doi: 10.7554/eLife.11182. PMID:26623517[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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