The High-Affinity Chymotrypsin Inhibitor Eglin C Poorly Inhibits Human Chymotrypsin-Like Protease: Gln192 and Lys218 Are Key Determinants
Structural biology article published in Proteins (2024)
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.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Zusammenfassung
Molecular dynamics simulations identify Gln192 and Lys218 as key determinants causing weak inhibition of human chymotrypsin-like protease (CTRL) by leech-derived eglin C, refining understanding of substrate specificity in serine proteases.
Warum dies für die Hirudotherapie relevant ist
This study examined why eglin C—a small protein from the medicinal leech long regarded as a general high-affinity inhibitor of chymotrypsins and elastases—weakly inhibits human chymotrypsin-like protease (CTRL) by several orders of magnitude compared with other chymotrypsins. Using comparative molecular dynamics simulations on bovine CTRA and human CTRL structures, the authors identified amino-acid positions 192 and 218 as key determinants shaping the S1 substrate-binding pocket and affecting protease-inhibitor complex stability. This is relevant to ASH's domain insofar as eglin C is a characterized leech-secretome inhibitor, and the work refines understanding of its target selectivity. Caveat: the study is computational/in silico (molecular dynamics), provides structural-mechanistic insight only, and offers no therapeutic or in-vivo data.
Zitation
The High-Affinity Chymotrypsin Inhibitor Eglin C Poorly Inhibits Human Chymotrypsin-Like Protease: Gln192 and Lys218 Are Key Determinants.
Németh BZ, Kiss B, Sahin-Tóth M, Magyar C, Pál G · Proteins, 2024
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