6IYC

Recognition of the Amyloid Precursor Protein by Human gamma-secretase


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 2.60 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 2.0 of the entry. See complete history


Literature

Recognition of the amyloid precursor protein by human gamma-secretase.

Zhou, R.Yang, G.Guo, X.Zhou, Q.Lei, J.Shi, Y.

(2019) Science 363

  • DOI: https://doi.org/10.1126/science.aaw0930
  • Primary Citation of Related Structures:  
    6IYC

  • PubMed Abstract: 

    Cleavage of amyloid precursor protein (APP) by the intramembrane protease γ-secretase is linked to Alzheimer's disease (AD). We report an atomic structure of human γ-secretase in complex with a transmembrane (TM) APP fragment at 2.6-angstrom resolution. The TM helix of APP closely interacts with five surrounding TMs of PS1 (the catalytic subunit of γ-secretase). A hybrid β sheet, which is formed by a β strand from APP and two β strands from PS1, guides γ-secretase to the scissile peptide bond of APP between its TM and β strand. Residues at the interface between PS1 and APP are heavily targeted by recurring mutations from AD patients. This structure, together with that of γ-secretase bound to Notch, reveal contrasting features of substrate binding, which may be applied toward the design of substrate-specific inhibitors.


  • Organizational Affiliation

    Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
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 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ92542
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Presenilin-1467Homo sapiensMutation(s): 1 
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 
Entity Groups  
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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 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
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
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Entity ID: 5
MoleculeChains Sequence LengthOrganismDetailsImage
Amyloid-beta A4 protein104Homo sapiensMutation(s): 1 
Gene Names: APPA4AD1
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P05067 (Homo sapiens)
Explore P05067 
Go to UniProtKB:  P05067
PHAROS:  P05067
GTEx:  ENSG00000142192 
Entity Groups  
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UniProt GroupP05067
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 6
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
F, H, I, J, K
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Entity ID: 7
MoleculeChains Length2D Diagram Glycosylation3D Interactions
beta-D-mannopyranose-(1-3)-[beta-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
G
5N-Glycosylation
Glycosylation Resources
GlyTouCan:  G89225LT
GlyCosmos:  G89225LT
GlyGen:  G89225LT
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
PC1
Query on PC1

Download Ideal Coordinates CCD File 
R [auth B],
V [auth C]
1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
C44 H88 N O8 P
NRJAVPSFFCBXDT-HUESYALOSA-N
CLR
Query on CLR

Download Ideal Coordinates CCD File 
S [auth C],
T [auth C],
U [auth C]
CHOLESTEROL
C27 H46 O
HVYWMOMLDIMFJA-DPAQBDIFSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
L [auth A]
M [auth A]
N [auth A]
O [auth A]
P [auth A]
L [auth A],
M [auth A],
N [auth A],
O [auth A],
P [auth A],
Q [auth A]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 2.60 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

Structure Validation

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Natural Science Foundation of ChinaChina31621092

Revision History  (Full details and data files)

  • Version 1.0: 2019-01-23
    Type: Initial release
  • Version 1.1: 2019-03-06
    Changes: Data collection, Database references
  • Version 1.2: 2019-11-06
    Changes: Data collection, Other
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Derived calculations, Structure summary