Research Faculty

P&S 7-430
630 West 168th St.
New York, NY 10032

Phone: 212-342-0115
Fax: 212-305-8780
Education and Training
Ph.D. 1999 Harvard University
Qing R. Fan, Ph.D.
Assistant Professor of Pharmacology and Pathology
and Cell Biology
Research Summary

Structural biology; cell surface receptor-ligand recognition.

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 GABAβ 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 GABAβ receptor that involves the formation of a novel heterodimer interface between subunits.

Selected Publications

Geng, Y., Mosyak, L., Kurinov, I., Zuo, H., Sturchler, E. Cheng, T.C., Subramanyam, P., Brown, A.P., Brennan, S.C., Mun, H., Bush, M., Chen, Y., Nguyen, T.X., Cao, B., Chang, D.D., Quick, M., Conigrave, A.D., Colecraft, H.M., McDonald, P. and Fan, Q.R. Structural mechanism of ligand activation in human calcium-sensing receptor. eLife. 5, e13662 (2016).

Burmakina, S., Geng, Y., Chen, Y., and Fan, Q.R.* Heterodimeric coiled-coil interactions of the human GABAB receptor. Proc. Natl. Acad. Sci. USA. 111, 6958-6963 (2014).

Geng, Y., Bush, M., Mosyak, L., Wang, F., and Fan, Q.R.. Structural mechanism of ligand activation in human GABAB receptor. Nature 504, 254-259 (2013).

Geng, Y., Xiong, D., Mosyak, L., Malito, D. L., Kniazeff, J., Chen, Y., Burmakina, S., Quick, M., Bush, M., Javitch, J. A., Pin, J.-P., and Fan, Q. R.. Structure and functional interaction of the extracellular domain of human GABAB receptor GBR2. Nature Neuroscience 15, 970-978 (2012).

Fan, Q. R. and Hendrickson, W. A. “Structure of human follicle-stimulating hormone in complex with its receptor” Nature 433, 269-277 (2005).

Fan, Q. R., Long, E. O. and Wiley, D. C. “Crystal structure of the human natural killer cell inhibitory receptor KIR2DL1 bound to its class I MHC ligand” Nature Immunology 2, 452-460 (2001).

Fan, Q. R., Mosyak, L., Winter, C. C., Wagtmann, N., Long, E. O. and Wiley, D. C. “Structure of the inhibitory receptor for human natural killer cells resembles haematopoietic receptors” Nature 389, 96-100 (1997).

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