5FN2

Cryo-EM structure of gamma secretase in complex with a drug DAPT


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 4.20 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Sampling the conformational space of the catalytic subunit of human gamma-secretase.

Bai, X.C.Rajendra, E.Yang, G.Shi, Y.Scheres, S.H.

(2015) Elife 4

  • DOI: https://doi.org/10.7554/eLife.11182
  • Primary Citation of Related Structures:  
    5FN2, 5FN3, 5FN4, 5FN5

  • 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.


  • Organizational Affiliation

    MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nicastrin709Homo sapiensMutation(s): 0 
Gene Names: NCSTNKIAA0253UNQ1874/PRO4317
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for Q92542 (Homo sapiens)
Explore Q92542 
Go to UniProtKB:  Q92542
PHAROS:  Q92542
GTEx:  ENSG00000162736 
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UniProt GroupQ92542
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Presenilin-1467Homo sapiensMutation(s): 0 
Gene Names: PSEN1AD3PS1PSNL1
EC: 3.4.23
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P49768 (Homo sapiens)
Explore P49768 
Go to UniProtKB:  P49768
PHAROS:  P49768
GTEx:  ENSG00000080815 
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UniProt GroupP49768
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Gamma-secretase subunit APH-1A265Homo sapiensMutation(s): 0 
Gene Names: APH1APSFCGI-78UNQ579/PRO1141
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for Q96BI3 (Homo sapiens)
Explore Q96BI3 
Go to UniProtKB:  Q96BI3
PHAROS:  Q96BI3
GTEx:  ENSG00000117362 
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UniProt GroupQ96BI3
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  • Reference Sequence
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Gamma-secretase subunit PEN-2101Homo sapiensMutation(s): 0 
Gene Names: PSENENPEN2MDS033
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for Q9NZ42 (Homo sapiens)
Explore Q9NZ42 
Go to UniProtKB:  Q9NZ42
PHAROS:  Q9NZ42
GTEx:  ENSG00000205155 
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UniProt GroupQ9NZ42
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 4.20 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-12-16
    Type: Initial release
  • Version 1.1: 2016-12-21
    Changes: Database references
  • Version 1.2: 2019-09-04
    Changes: Data collection, Database references, Source and taxonomy, Structure summary