期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 25, 页码 10171-10176出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1300457110
关键词
hexokinase; sigmoidicity I conformational restriction; type 2 diabetes
资金
- Pioneer Research Center Program [2008-2000218]
- Advanced Biomass RD Center [2011-0031363]
- Intelligent Synthetic Biology Center through the National Research Foundation of Korea [2011-0031950]
- Ministry of Science, Information and Communication Technology and Future Planning
- World-Class University (WCU) program
- Brain Korea 21 of the Ministry of Education (Korea)
- National Research Foundation of Korea [2011-0031950] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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.
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