EMD-32717

Single-particle
3.1 Å
EMD-32717 Deposition: 26/01/2022
Map released: 26/10/2022
Last modified: 30/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-32717

Structure of Inhibited-EP

EMD-32717

Single-particle
3.1 Å
EMD-32717 Deposition: 26/01/2022
Map released: 26/10/2022
Last modified: 30/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: inhibited-EP
Fitted models: 7wr7 (Avg. Q-score: 0.427)

Deposition Authors: Yang XL, Ding ZY, Huang HJ
Cryo-EM structures reveal the activation and substrate recognition mechanism of human enteropeptidase.
Yang X, Ding Z , Peng L , Song Q , Zhang D , Cui F , Xia C , Li K , Yin H , Li S , Li Z , Huang H
(2022) Nat Commun , 13 , 6955 - 6955
PUBMED: 36376282
DOI: doi:10.1038/s41467-022-34364-9
ISSN: 2041-1723
Abstract:
Enteropeptidase (EP) initiates intestinal digestion by proteolytically processing trypsinogen, generating catalytically active trypsin. EP dysfunction causes a series of pancreatic diseases including acute necrotizing pancreatitis. However, the molecular mechanisms of EP activation and substrate recognition remain elusive, due to the lack of structural information on the EP heavy chain. Here, we report cryo-EM structures of human EP in inactive, active, and substrate-bound states at resolutions from 2.7 to 4.9 Å. The EP heavy chain was observed to clamp the light chain with CUB2 domain for substrate recognition. The EP light chain N-terminus induced a rearrangement of surface-loops from inactive to active conformations, resulting in activated EP. The heavy chain then served as a hinge for light-chain conformational changes to recruit and subsequently cleave substrate. Our study provides structural insights into rearrangements of EP surface-loops and heavy chain dynamics in the EP catalytic cycle, advancing our understanding of EP-associated pancreatitis.