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- Title
Kinetic Cooperativity in Human Pancreatic Glucokinase Originates from Millisecond Dynamics of the Small Domain.
- Authors
Larion, Mioara; Hansen, Alexandar L.; Zhang, Fengli; Bruschweiler-Li, Lei; Tugarinov, Vitali; Miller, Brian G.; Brüschweiler, Rafael
- Abstract
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 40 years 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 kex value of 509±51 s-1, whereas in the glucosebound 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.
- Subjects
GLUCOKINASE; PHOSPHORYLATION; GLUCOSE; GLYCOLYSIS; ADENOSINE triphosphatase; ISOLEUCINE; NUCLEAR magnetic resonance spectroscopy
- Publication
Angewandte Chemie, 2015, Vol 127, Issue 28, p8247
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/anie.201501204