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Substrate Conformational Dynamics in Proteolysis
Author(s) -
Radisky Evette S.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.412.1
Subject(s) - proteolysis , chemistry , proteases , conformational change , enzyme , protease , molecular dynamics , protein dynamics , substrate (aquarium) , protein structure , biophysics , biochemistry , proteolytic enzymes , biology , computational chemistry , ecology
Enzyme catalytic power and specificity derive from dynamic interactions between enzymes and their substrates. While considerable effort has been devoted to understanding how enzyme conformational dynamics can affect catalysis, the importance of conformational dynamics within protein substrates has been overlooked. Proteases are ubiquitous enzymes that catalyze the hydrolysis of peptide bonds within protein substrates; they have served as key model enzymes for studying the molecular basis for catalysis and specificity. Recent work from our research group, focusing on trypsins and chymotrypsins as model proteolytic enzymes, reveals that differing conformational dynamics in otherwise similar protein substrates can profoundly impact proteolysis. In this talk, I will present some of our recent findings, integrating evidence from crystal structures, molecular dynamics simulations, and enzyme kinetics studies, which implicate flexibility and conformational motions of protease substrates as critical determinants of proteolysis. Our studies suggest that specific substrate conformational dynamics have evolved to regulate biological proteolytic events. More generally, our work suggests that we must look beyond enzymes, and examine substrates also, to fully appreciate the importance of protein dynamics in enzyme catalysis. Support or Funding Information Supported by NIH grant R01CA154387.