[Ligand recognition mechanism of G-CSF receptor and metabotropic glutamate receptor].

A three-dimensional view of ligand-receptor recognition at the atomic level is crucial to understand the molecular mechanism of receptor activation. This review describes the structure-function relationships of two receptors important for pharmaceutical science. Granulocyte colony-stimulating factor (G-CSF) is the principal growth factor regulating the maturation, proliferation, and differentiation of the precursor cells of neutrophilic granulocytes. We have determined the crystal structure of G-CSF complexed to the BN-BC domains, the principal ligand binding region of the G-CSF receptor. In a novel oligomerization scheme, the two receptor domains complex in a 2:2 ratio to the ligand, with a noncrystallographic pseudo-two-fold axis through primarily the interdomain region and secondarily the BC domain. This first structural view of a gp130-type receptor-ligand complex presents a new molecular basis for cytokine-receptor recognition. The metabotropic glutamate receptors (mGluRs) are key receptors in the modulation of excitatory synaptic transmission in the central nervous system. Three different crystal structures of the extracellular ligand-binding region (LBR) of mGluR1 have been determined, in a complex with glutamate and in two unliganded forms. They all showed disulfide-linked homo-dimers, of which the "active" and "resting" conformations are modulated through the novel dimeric interface by a packed alpha-helical structure. The bilobed protomer architectures flexibly change their domain arrangements between an "open" or "closed" conformation. Glutamate binding stabilizes both the "active" dimer and "closed" protomer in dynamic equilibrium. Four domain movements within the dimer affect the separation of the transmembrane and intracellular regions and thereby activate the receptor.