Molecular determinants of allosteric modulation of protein disulfide isomerase by small-molecule b'-ligands.

ABSTRACT: Allosteric modulation is central to enzyme function and an attractive strategy for drug development. Protein Disulfide Isomerase (PDI), the prototypical thiol-isomerase, exemplifies this potential through its structural flexibility and involvement in neurodegeneration, cancer, and thromboinflammatory disorders such as sepsis, stroke, cancer-associated thrombosis, and antiphospholipid syndrome. PDI consists of four thioredoxin-like domains (a-b-b'-a'), with catalytic CGHC motifs in a and a' domains and a ligand-binding pocket in the b' domain. We previously reported that the b'-ligand bepristat 2a (Bep2a) inhibits PDI activity toward large macromolecular substrates while allosterically enhancing activity toward smaller physiological substrates such as GSSG and l-cystine. Here, we define the

SUBMITTER: Ponzar N 

PROVIDER: S-EPMC12870469 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature