Qing R. Fan, PhD

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Overview

Academic Appointments

  • Associate Professor of Pharmacology and Pathology and Cell Biology

Research

Our laboratory studies the molecular mechanisms by which class C G-protein coupled receptors (GPCRs) transmit signals across biological membranes. Class C GPCRs mediate a number of key biological phenomena including excitatory and inhibitory neurotransmission, calcium homeostasis, taste and smell. These receptors are characterized by a large ligand-binding extracellular domain in addition to the canonical seven-helix transmembrane domain. Another unique feature of the class C receptors is that they require dimerization for function. We are investigating the structure and function of two class C GPCRs, human GABA(B) receptor and calcium-sensing receptor (CaSR). Our goal is to understand the ligand-dependent activation mechanism of these receptors.

Human GABA(B) receptor mediates inhibitory neurotransmission in the brain. It functions as an obligatory heterodimer of GBR1 and GBR2 subunits. 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. These structures reveal the molecular basis of ligand recognition by GABA(B) receptor. 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. GABA(B) receptor activation involves the formation of a novel heterodimer interface between subunits.

Human CaSR maintains extracellular Ca2+ homeostasis through the regulation of parathyroid hormone secretion. We solved the crystal structures of the entire extracellular domain of CaSR in the resting and active conformations. We provide direct evidence that L-amino acids are agonists of the receptor. In the active structure, L-Trp occupies the orthosteric agonist-binding site at the interdomain cleft, and is primarily responsible for inducing extracellular domain closure to initiate receptor activation. Our structures reveal multiple binding sites for Ca2+ and PO43- ions. While Ca2+ ions stabilize the active state, PO43- ions reinforce the inactive conformation.

Our data suggest a universal activation mechanism for class C GPCRS that involves extracellular domain closure and association of membrane-proximal domains.

Research Interests

  • Structural biology; cell surface receptor - ligand recognition

Grants

MECHANISM OF ACTIVATION AND MODULATION IN HUMAN GABA(B) RECEPTOR (Federal Gov)

Sep 1 2018 - Jul 31 2022

STRUCTURAL ANALYSIS OF ALCOHOL-DEPENDENT ACTIVATION OF GIRKS (Federal Gov)

Apr 15 2016 - Mar 31 2021

MOLECULAR MECHANISMS OF HUMAN EXTRACELLULAR CALCIUM-SENSING RECEPTOR FUNCTION (Private)

Jul 1 2015 - Jun 30 2018

STRUCTURAL STUDIES OF METABOTROPIC GABA RECEPTORS (Federal Gov)

Aug 15 2009 - Aug 31 2016

MOLECULAR MECHANISM OF METABOTROPIC GABA RECEPTOR FUNCTION. MCKNIGHT SCHOLAR AWARDS (Private)

Jul 1 2011 - Jun 30 2014

STRUCTURAL STUDIES OF HUMAN GABA(B) RECEPTORS (Private)

Jul 1 2009 - Jun 30 2014

THE STRUCTURAL STUDIES OF GABAB RECEPTORS. (Private)

Jan 1 2009 - Dec 31 2013

STRUCTURAL AND FUNCTIONAL ANALYSIS OF HUMAN GABA (B) RECEPTO RS (Private)

Jul 1 2008 - Jun 30 2013

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., 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).