7wqx

From Proteopedia

Structure of Inactive-EP

Structural highlights

7wqx is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.7Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ENTK_HUMAN Congenital enteropathy due to enteropeptidase deficiency. The disease is caused by mutations affecting the gene represented in this entry.

Function

ENTK_HUMAN Responsible for initiating activation of pancreatic proteolytic proenzymes (trypsin, chymotrypsin and carboxypeptidase A). It catalyzes the conversion of trypsinogen to trypsin which in turn activates other proenzymes including chymotrypsinogen, procarboxypeptidases, and proelastases.

Publication Abstract from PubMed

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 A. 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.

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 Nat Commun. 2022 Nov 14;13(1):6955. doi: 10.1038/s41467-022-34364-9. PMID:36376282^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Yang X, Ding Z, Peng L, Song Q, Zhang D, Cui F, Xia C, Li K, Yin H, Li S, Li Z, Huang H. Cryo-EM structures reveal the activation and substrate recognition mechanism of human enteropeptidase. Nat Commun. 2022 Nov 14;13(1):6955. doi: 10.1038/s41467-022-34364-9. PMID:36376282 doi:http://dx.doi.org/10.1038/s41467-022-34364-9