The High-Affinity Chymotrypsin Inhibitor Eglin C Poorly Inhibits Human Chymotrypsin-Like Protease: Gln192 and Lys218 Are Key Determinants

Eglin C, a small protein from the medicinal leech, has been long considered a general high-affinity inhibitor of chymotrypsins and elastases. Here, we demonstrate that eglin C inhibits human chymotrypsin-like protease (CTRL) weaker by several orders of magnitude than other chymotrypsins. In order to...

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Published inProteins, structure, function, and bioinformatics
Main Authors Németh, Bálint Zoltán, Kiss, Bence, Sahin-Tóth, Miklós, Magyar, Csaba, Pál, Gábor
Format Journal Article
LanguageEnglish
Published United States 20.09.2024
Subjects
protein–protein interaction
eglin C
human chymotrypsin‐like enzyme
molecular dynamics
serine proteinase inhibitor
serine proteinase
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Summary:Eglin C, a small protein from the medicinal leech, has been long considered a general high-affinity inhibitor of chymotrypsins and elastases. Here, we demonstrate that eglin C inhibits human chymotrypsin-like protease (CTRL) weaker by several orders of magnitude than other chymotrypsins. In order to identify the underlying structural aspects of this unique deviation, we performed comparative molecular dynamics simulations on experimental and AlphaFold model structures of bovine CTRA and human CTRL. Our results indicate that in CTRL, the primary determinants of the observed weak inhibition are amino-acid positions 192 and 218 (using conventional chymotrypsin numbering), which participate in shaping the S1 substrate-binding pocket and thereby affect the stability of the protease-inhibitor complexes.
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ISSN:0887-3585
1097-0134
1097-0134
DOI:10.1002/prot.26750