A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies.
molecular dynamics simulations
replica exchange
transition path sampling
trypsin
umbrella sampling
Journal
Journal of inflammation research
ISSN: 1178-7031
Titre abrégé: J Inflamm Res
Pays: New Zealand
ID NLM: 101512684
Informations de publication
Date de publication:
2021
2021
Historique:
received:
01
02
2021
accepted:
24
03
2021
entrez:
31
5
2021
pubmed:
1
6
2021
medline:
1
6
2021
Statut:
epublish
Résumé
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. Simulations with molecular dynamics, replica exchange, and transition pathway methods are used. 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. Based on our result, a hypothesis is formulated that explains the development of chronic pancreatitis through accelerated digestion of the mutant by trypsin.
Identifiants
pubmed: 34054303
doi: 10.2147/JIR.S304787
pii: 304787
pmc: PMC8157096
doi:
Types de publication
Journal Article
Langues
eng
Pagination
2111-2119Informations de copyright
© 2021 Kulke et al.
Déclaration de conflit d'intérêts
The authors report no conflicts of interest in this work.
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