Between Protein Fold and Nucleophile Identity: Multiscale Modeling of the TEV Protease Enzyme-Substrate Complex.

ABSTRACT: The cysteine protease from the tobacco etch virus (TEVp) is a well-known and widely utilized enzyme. TEVp's chymotrypsin-like fold is generally associated with serine catalytic triads that differ in terms of a reaction mechanism from the most well-studied papain-like cysteine proteases. The question of what dominates the TEVp mechanism, nucleophile identity, or structural composition has never been previously addressed. Here, we use enhanced sampling multiscale modeling to uncover that TEVp combines the features of two worlds in such a way that potentially hampers its activity. We show that TEVp cysteine is strictly in the anionic form in a free enzyme similar to papain. Peptide binding shifts the equilibrium toward the nucleophile's protonated form, characteristic of chymotrypsin-like pro

SUBMITTER: Zlobin A 

PROVIDER: S-EPMC9647873 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature