Fan Qing R

Biography

She is professsor at Columbia University.

Research Interest

Our laboratory studies the molecular mechanisms by which G-protein coupled receptors (GPCRs) transmit signals across biological membranes. GPCRs represent the superfamily of transmembrane receptors that signal through heterotrimeric G-proteins. GPCRs recognize a diverse array of ligands, and are the targets for 50-60% of clinical drugs. We combine x-ray crystallography with various biochemical techniques to study these receptors with two general goals: (1) to determine the specificity of receptor-ligand interactions, and (2) to identify receptor activation mechanisms. Human GABAB receptor is a G-protein coupled receptor central to inhibitory neurotransmission in the brain. It functions as an obligatory heterodimer of GBR1 and GBR2 subunits. Recently we determined the crystal structures of a heterodimeric complex between the extracellular domains of GBR1 and GBR2 in the apo, agonist-bound, and antagonist-bound forms. The apo and antagonist-bound structures represent the resting state of the receptor; the agonist-bound complex corresponds to the active state. Both subunits adopt an open conformation at rest, and only GBR1 closes upon agonist-induced receptor activation. The agonists and antagonists are anchored in the interdomain crevice of GBR1 by an overlapping set of residues. An antagonist confines GBR1 to the open conformation of the inactive state, while an agonist induces its domain closure for activation. Our data reveals a unique activation mechanism for GABAB receptor that involves the formation of a novel heterodimer interface between subunits.