A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies

Overview

Journal J Inflamm Res

Publisher Dove Medical Press

Date 2021 May 31

PMID 34054303

Citations 2

Authors

Martin Kulke

Felix Nagel

Lukas Schulig

Norman Geist

Marcel Gabor

Julia Mayerle

Markus M Lerch

Andreas Link

Mihaela Delcea

Affiliations

Soon will be listed here.

Abstract

Purpose: Although strongly related, the pathophysiological effect of the N34S mutation in the serine protease inhibitor Kazal type 1 (SPINK1) in chronic pancreatitis is still unknown. In this study, we investigate the conformational space of the human cationic trypsin-serine protease inhibitor complex.

Methods: Simulations with molecular dynamics, replica exchange, and transition pathway methods are used.

Results: Two main binding states of the inhibitor to the complex were found, which explicitly relate the influence of the mutation site to conformational changes in the active site of trypsin.

Conclusion: Based on our result, a hypothesis is formulated that explains the development of chronic pancreatitis through accelerated digestion of the mutant by trypsin.

Citing Articles

Structural and Biophysical Insights into SPINK1 Bound to Human Cationic Trypsin.

Nagel F, Palm G, Geist N, McDonnell T, Susemihl A, Girbardt B Int J Mol Sci. 2022; 23(7).

PMID: 35408828 PMC: 8998336. DOI: 10.3390/ijms23073468.

Chronic Pancreatitis: The True Pathogenic Culprit within the N34S-Containing Haplotype Is No Longer at Large.

Pu N, Masson E, Cooper D, Genin E, Ferec C, Chen J Genes (Basel). 2021; 12(11).

PMID: 34828289 PMC: 8619230. DOI: 10.3390/genes12111683.

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