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 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.

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.

Leech-derived molecules this paper discusses, each with a full profile in the ASH compound registry:

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