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

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 compl...

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Autores principales: Kulke, Martin, Nagel, Felix, Schulig, Lukas, Geist, Norman, Gabor, Marcel, Mayerle, Julia, M Lerch, Markus, Link, Andreas, Delcea, Mihaela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2021
Materias:
Hypothesis
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157096/
https://www.ncbi.nlm.nih.gov/pubmed/34054303
http://dx.doi.org/10.2147/JIR.S304787
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author Kulke, Martin
Nagel, Felix
Schulig, Lukas
Geist, Norman
Gabor, Marcel
Mayerle, Julia
M Lerch, Markus
Link, Andreas
Delcea, Mihaela
author_facet Kulke, Martin
Nagel, Felix
Schulig, Lukas
Geist, Norman
Gabor, Marcel
Mayerle, Julia
M Lerch, Markus
Link, Andreas
Delcea, Mihaela
author_sort Kulke, Martin
collection PubMed
description 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.
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spelling pubmed-81570962021-05-28 A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies Kulke, Martin Nagel, Felix Schulig, Lukas Geist, Norman Gabor, Marcel Mayerle, Julia M Lerch, Markus Link, Andreas Delcea, Mihaela J Inflamm Res Hypothesis 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. Dove 2021-05-21 /pmc/articles/PMC8157096/ /pubmed/34054303 http://dx.doi.org/10.2147/JIR.S304787 Text en © 2021 Kulke et al. https://creativecommons.org/licenses/by/4.0/This work is published by Dove Medical Press Limited, and licensed under a Creative Commons Attribution License. The full terms of the License are available at http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Hypothesis
Kulke, Martin
Nagel, Felix
Schulig, Lukas
Geist, Norman
Gabor, Marcel
Mayerle, Julia
M Lerch, Markus
Link, Andreas
Delcea, Mihaela
A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies
title A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies
title_full A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies
title_fullStr A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies
title_full_unstemmed A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies
title_short A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies
title_sort hypothesized mechanism for chronic pancreatitis caused by the n34s mutation of serine protease inhibitor kazal-type 1 based on conformational studies
topic Hypothesis
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157096/
https://www.ncbi.nlm.nih.gov/pubmed/34054303
http://dx.doi.org/10.2147/JIR.S304787
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