Qing R. Fan, PhD

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Overview

Academic Appointments

  • Associate Professor of Pharmacology and Pathology and Cell Biology

Credentials & Experience

Education & Training

  • PhD, MA, BA, Chemistry, Harvard University

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, and taste. 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 (CaS) receptor. 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 extracellular-domain structures of GABA(B) receptor in three functional states: in the apo form, bound to six different antagonists, and bound to two different agonists. Our structures revealed the molecular mechanisms of orthosteric ligand recognition and showed that receptor activation involves the formation of a novel heterodimer interface between membrane proximal-domains of both subunits.

We recently solved a near full-length structure of GABA(B) receptor, captured in the inactive state by cryo-electron microscopy. Our structure revealed a novel heterodimer interface between the transmembrane (TM) helices 3 and 5 of both GABA(B) subunits. This interface embodies the signature of GABA(B) receptor’s inactive conformation. Furthermore, we identified a unique ¢intersubunit latch¢ motif within this TM interface that maintains the inactive state of the receptor. Its disruption through mutation results in constitutive receptor activity. We also discovered multiple ligands pre-associated with the receptor, including two large endogenous phospholipids embedded within the TM domains to modulate receptor function and maintain receptor integrity.

Human CaS receptor maintains extracellular Ca(2+) homeostasis through the regulation of parathyroid hormone secretion. We solved the crystal structures of the entire extracellular domain of CaS receptor in the resting and active conformations. We provided 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.

Using anomalous difference maps, we identified multiple novel binding sites for Ca(2+) that are located throughout the extracellular domain. Ca(2+) fulfills two functional roles. First, it maintains the structural integrity of CaS receptor. Second, it is directly involved in receptor activation as it facilitates the formation of a homodimer interface that is unique to the active state. Our results indicate that amino acids and Ca(2+) are co-agonists of CaS receptor, acting jointly to trigger receptor activation.

Our structures revealed multiple binding sites for PO4(3-). PO4(3-) is also important for structural integrity of the receptor, but it inhibits receptor activity. Therefore, activation of CaS receptor involves an intricate interplay of amino acids, Ca(2+), and PO4(3-).

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

STRUCTURAL STUDIES OF HUMAN EXTRACELLULAR CALCIUM-SENSING RECEPTOR (Federal Gov)

Aug 1 2015 - Jun 30 2020

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

1.  Park, J., Fu Z., Frangaj, A., Liu, J., Mosyak, L., Shen, T., Slavkovich, V.N., Ray, K.M., Taura, J., Cao, B., Geng, Y., Zuo, H., Kou, Y., Grassucci, R., Chen, S., Liu, Z., Lin, X., Williams, J.P., Rice, W.J., Eng, E.T., Huang, R.K., Soni, R.K., Kloss, B., Yu, Z., Javitch, J.A., Hendrickson, W.A., Slesinger, P.A., Quick, M., Graziano, J., Yu, H., Fiehn, O., Clarke, O.B., Frank, J., Fan, Q.R. Structure of human GABAB receptor in an inactive state. Nature, doi: 10.1038/s41586-020-2452-0 (2020). PMID: 32581365. 

2.  Zuo, H., Glaaser, I., Zhao, Y., Kourinov, I., Mosyak, L., Wang, H., Liu, J., Park, J., Frangaj, A., Sturchler, E., Zhou, M., McDonald, P., Geng, Y., Slesinger, P.A. and Fan, Q.R. Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor. Proc. Natl. Acad. Sci. USA. 116, 8370-8379 (2019). PMID: 30971491.

3.   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). PMID: 27434672.

4.   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). PMID: 24778228.

5.   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). PMID: 24305054.

6.  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). PMID: 22660477.