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

Bálint Zoltán Németh; Bence Kiss; Miklós Sahin-Tóth; Csaba Magyar; Gábor Pál

doi:10.1002/prot.26750

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

Proteins. 2024 Sep 20. doi: 10.1002/prot.26750. Online ahead of print.

Authors

Bálint Zoltán Németh^{1

2}, Bence Kiss¹, Miklós Sahin-Tóth³, Csaba Magyar², Gábor Pál¹

Affiliations

¹ Department of Biochemistry, ELTE Eötvös Loránd University, Budapest, Hungary.
² Institute of Molecular Life Sciences, Protein Bioinformatics Research Group, Hungarian Research Network, Budapest, Hungary.
³ Department of Surgery, University of California Los Angeles, California, Los Angeles, USA.

PMID: 39301701
DOI: 10.1002/prot.26750

Abstract

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.

Keywords: eglin C; human chymotrypsin‐like enzyme; molecular dynamics; protein–protein interaction; serine proteinase; serine proteinase inhibitor.

Abstract

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