Glucokinase is a monomeric enzyme that displays a low affinity for glucose and a sigmoidal saturation curve for its substrate, two properties that are important for its playing the role of a glucose sensor in pancreas and liver. The molecular basis for these two properties is not well understood. Herein we report the crystal structures of glucokinase in its active and inactive forms, which demonstrate that global conformational change, including domain reorganization, is induced by glucose binding. This suggests that the positive cooperativity of monomeric glucokinase obeys the "mnemonical mechanism" rather than the well-known concerted model. These structures also revealed an allosteric site through which small molecules may modulate the kinetic properties of the enzyme. This finding provided the mechanistic basis for activation of glucokinase as a potential therapeutic approach for treating type 2 diabetes mellitus.

Novel isoxazolopyridone derivatives that are metabotropic glutamate receptor (mGluR) 7 antagonists were discovered and pharmacologically characterized. 5-Methyl-3,6-diphenylisoxazolo [4,5-c]pyridin-4(5H)-one (MDIP) was identified by random screening, and 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo [4,5-c] In CHO cells coexpressing human mGluR7 with G␣ 15 , MDIP and MMPIP also inhibited the L-AP4-induced cAMP response. The maximal degree of inhibition by MMPIP was higher than that by MDIP in a cAMP assay. MMPIP was able to antagonize an allosteric agonist, the N,NЈ-dibenzhydryl-ethane-1,2-diamine dihydrochloride (AMN082)-induced inhibition of cAMP accumulation. In the absence of these agonists, MMPIP caused a further increase in forskolin-stimulated cAMP levels in CHO cells expressing mGluR7, whereas a competitive antagonist, LY341495, did not. This result indicates that MMPIP has an inverse agonistic activity. The intrinsic activity of MMPIP was pertussis toxin-sensitive and mGluR7-dependent. MMPIP at concentrations of at least 1 M had no significant effect on mGluR1, mGluR2, mGluR3, mGluR4, mGluR5, and mGluR8. MMPIP is the first allosteric mGluR7-selective antagonist that could potentially be useful as a pharmacological tool for elucidating the roles of mGluR7 on central nervous system functions.Metabotropic glutamate receptors (mGluRs) belong to a family of G protein-coupled receptors thought to contribute to the modulation of neuronal excitability and neurotransmitter release. Eight mGluR subtypes (mGluR1-mGluR8) have been cloned, and they have been classified into three groups based on sequence homology, pharmacological profile, and signal transduction pathway. mGluR1 and mGluR5 belong to group I mGluRs, and they are coupled to phospholipase C and subsequent intracellular calcium release via G q protein. mGluR2 and mGluR3 belong to group II mGluRs, whereas mGluR4, mGluR6, mGluR7, and mGluR8 belong to group III mGluRs. The subtypes of group II and group III mGluRs are negatively coupled to adenylate cyclase via G i protein (Conn and Pin, 1997 , 5-methyl-3,6-diphenylisoxazolo[4,5-c

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