期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 54, 期 28, 页码 8129-8132出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201501204
关键词
allostery; enzyme catalysis; kinetic cooperativity; NMR spectroscopy; time-resolved conformational dynamics
资金
- American Heart Association [12POST12040344]
- NIH [1R01K081358]
- NSF [MCB-1360966]
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1360966] Funding Source: National Science Foundation
The hallmark of glucokinase (GCK), which catalyzes the phosphorylation of glucose during glycolysis, is its kinetic cooperativity, whose understanding at atomic detail has remained open since its discovery over 40years ago. Herein, by using kinetic CPMG NMR spectroscopic data for 17 isoleucine side chains distributed over all parts of GCK, we show that the origin of kinetic cooperativity is rooted in intramolecular protein dynamics. Residues of glucose-free GCK located in the small domain displayed distinct exchange behavior involving multiple conformers that are substantially populated (p>17%) with a k(ex)value of 509 +/- 51s(-1), whereas in the glucose-bound form these exchange processes were quenched. This exchange behavior directly competes with the enzymatic turnover rate at physiological glucose concentrations, thereby generating the sigmoidal rate dependence that defines kinetic cooperativity.
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