Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase

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Glucokinase (GK) is a monomeric allosteric enzyme and plays a pivotal role in blood glucose homeostasis. GK is regulated by GK regulatory protein (GKRP), and indirectly by allosteric effectors of GKRP. Despite the critical roles of GK and GKRP, the molecular basis for the allosteric regulation mechanism of GK by GKRP remains unclear. We determined the crystal structure of Xenopus GK and GKRP complex in the presence of fructose-6-phosphate at 2.9 angstrom. GKRP binds to a super-open conformation of GK mainly through hydrophobic interaction, inhibiting the GK activity by locking a small domain of GK. We demonstrate the molecular mechanism for the modulation of GK activity by allosteric effectors of GKRP. Importantly, GKRP releases GK in a sigmoidal manner in response to glucose concentration by restricting a structural rearrangement of the GK small domain via a single ion pair. We find that GKRP acts as an allosteric switch for GK in blood glucose control by the liver.
Publisher
NATL ACAD SCIENCES
Issue Date
2013-06
Language
English
Article Type
Article
Keywords

TYPE-2 DIABETES-MELLITUS; LIVER GLUCOKINASE; HEPATIC GLUCOKINASE; CLINICAL CANDIDATE; GLUCOSE-PRODUCTION; FRUCTOSE; ACTIVATORS; GENE; IDENTIFICATION; METABOLISM

Citation

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.110, no.25, pp.10171 - 10176

ISSN
0027-8424
DOI
10.1073/pnas.1300457110
URI
http://hdl.handle.net/10203/193869
Appears in Collection
BS-Journal Papers(저널논문)
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