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

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.

SUBMITTER: Kulke M

PROVIDER: S-EPMC8157096 | biostudies-literature |

REPOSITORIES: biostudies-literature

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