About

Qing R. Fan, PhD, is a Professor of Molecular Pharmacology and Therapeutics, Pathology, and Cell Biology at Columbia University Vagelos College of Physicians and Surgeons. His laboratory studies the molecular mechanisms by which class C G protein-coupled receptors (GPCRs) transmit signals across biological membranes. His research focuses on understanding the structure and function of these receptors, including the human GABA(B) receptor and calcium-sensing (CaS) receptor, which are involved in key biological phenomena such as neurotransmission, calcium homeostasis, and taste. Dr. Fan's work has contributed to elucidating the ligand-dependent activation mechanisms of these receptors through structural biology approaches. He has determined the extracellular-domain structures of GABA(B) receptor in various states, revealing the molecular mechanisms of ligand recognition and receptor activation, including the formation of heterodimer interfaces and the identification of motifs that maintain receptor inactivity. His research also includes solving the crystal structures of the CaS receptor's extracellular domain, providing insights into how amino acids, calcium ions, and phosphate ions act as co-agonists or inhibitors, thereby regulating receptor activity. His contributions have advanced the understanding of GPCR signaling and receptor regulation at the molecular level.

Research topics

• Biology
• Chemistry
• Cell biology
• Biochemistry
• Biophysics
• Virology
• Genetics
• Immunology
• Medicine

Selected publications

• Molecular Characterization of Emerging Gyrovirus galga 1 from Poultry Markets of Guangxi, China

  International Journal of Molecular Sciences · 2026-02-09

  articleOpen access

  1 (GyG1) can infect a variety of animals and humans, but prevention and control strategies are limited, which endangers the healthy development of the poultry breeding industry and has a potential impact on public health safety. The live poultry market (LPM) connects the production and consumption ends, and the pathogen may spread across regions through transportation and personnel flow. To understand the prevalence of GyG1 in Guangxi, 3482 samples from LPMs, namely, 2693 chicken throat and cloacal swabs and 789 environmental samples collected in Guangxi from December 2019 to December 2024, were assayed by PCR. The results revealed that GyG1 was present in chicken and environmental samples from LPMs in Guangxi, China, with positivity rates of 17.08% and 13.31%, respectively. Eight GyG1-positive samples were randomly selected, including 5 chicken swab samples and 3 environmental samples for whole-genome amplification. The amino acids encoded by the three ORFs were analysed, and some mutation sites unique to these 8 variants were found. The homology between the 8 GyG1 genomes and 36 reference sequences was 96.8-99.8%. The homology of the VP1 gene sequence was 96.5-99.9%, and the homology of the amino acid sequence was 99.4-100%. A phylogenetic tree was constructed on the basis of the 8 GyG1 genomes and 36 GyG1 reference genome sequences from 14 different species (8 from zoos) in this study. The 44 sequences were divided into three branches constituting groups A, B and C, with the 8 novel strains classified into group A2. Recombination analysis predicted that two recombination events in the GyG1 sequence were associated with the emergence of Guangxi strain GX-AGV2-202109-5. This study clarified the prevalence and molecular characteristics of GyG1 in LPMs in Guangxi, China, were clarified for the first time, providing important data supporting the prevention and control of GyG1 infection and providing a reference for further understanding the epidemiology and genetic diversity of GyG1.

  PublisherOA PDFDOI

• Reprogramming insulin receptor activation with a de novo agonist to overcome severe insulin resistance

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-07

  articleOpen access

  Computational protein engineering provides a powerful approach to address longstanding clinical challenges. Severe insulin resistance syndromes caused by mutations in the insulin receptor (IR) are life-threatening disorders for which effective long-term therapies remain lacking. Here, we define the in vivo activity and therapeutic potential of RF-409, a de novo-designed IR agonist that activates the receptor through a mechanism distinct from insulin. RF-409 exhibits markedly prolonged circulation compared to insulin and produces sustained improvements in glucose homeostasis without detectable adverse effects on body composition or liver function. In a patient-derived IR D707A mouse model of severe insulin resistance, RF-409-but not insulin-activates the mutant receptor, restoring glucose regulation and ameliorating hyperglycemia, hyperinsulinemia, lipoatrophy, and pancreatic atrophy. Mechanistically, RF-409 engages the IR through a noncanonical binding geometry while stabilizing an active conformation resembling that induced by insulin. Phosphoproteomic profiling shows that RF-409 elicits broadly insulin-like signaling with distinct temporal features in receptor-proximal regulation. Together, these findings establish a framework for reactivating dysfunctional receptors and suggest broader applications beyond rare receptoropathies, including diabetes and liver disease.

  PublisherDOI

• Rapid clonal expansion and somatic hypermutation contribute to the fate of SARS-CoV-2 broadly neutralizing antibodies

  The Journal of Immunology · 2025-02-01 · 3 citations

  articleOpen access

  Several vaccines and immunization strategies, including inactivated vaccines, have proven effective in eliciting antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), providing an opportunity to characterize the antibody response. In this study, we investigated the monoclonal antibody responses elicited by wild-type SARS-CoV-2 inactivated vaccination compared to those elicited by natural infection and mRNA vaccination. The analysis showed that antibodies encoded by biased germline genes were shared between SARS-CoV-2 vaccinated and naturally infected individuals. Among the 35 shared clonotypes identified, besides the well-known IGHV3-53 and IGHV1-58, we identified a class of IGHV4-59 antibodies characterized by rapid response and neutralizing activity, elicited by 3 doses of inactivated vaccine. Members of this lineage exhibited similar sensitivity against wild-type SARS-CoV-2, whereas different neutralizing activities against SARS-CoV-2 variants, especially against various Omicron subvariants, BA.1, BA.2, BA.2.12.1, BA.4/5, and BA.2.75. Structural analysis of BA.1 spike complexed with VacBB-639 revealed that the IGHV4-59-lineage antibodies belonged to the Class 2/3 group. Using sequence alignment, site-mutation assays, and functional verification, we identified two substitutions, N60K in HFR3 and S56G in HCDR2, contributing to opposite neutralization changes of IGHV4-59-lineage antibodies against these Omicron subvariants. These results demonstrate the importance of somatic hypermutation in the evolution of prototypical antigen-elicited antibodies in terms of their neutralization breadth and potency against SARS-CoV-2 Omicron variants.

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• Structure of an LGR dimer, an evolutionary predecessor of glycoprotein hormone receptors

  Nature Communications · 2025-11-28 · 1 citations

  articleOpen access

  Glycoprotein hormones (GpHs) produced in the human pituitary act through receptors (GpHRs) in the gonads to support reproduction and in the thyroid for metabolism. GpHs are heterodimeric cystine-knot proteins; their receptors bind cognate hormones at an extracellular domain and signal through a transmembrane domain to heterotrimeric G proteins. GpHs and GpHRs have co-evolved from invertebrate counterparts. Structures of the human receptors as isolated for cryogenic electron microscopy (cryo-EM) are all monomeric despite compelling evidence for their functioning as dimers. Here we characterize the homologous receptor from Caenorhabditis elegans. Its biochemical properties are notably similar to those of the thyroid stimulating hormone receptor (TSHR) of humans. Structurally, it is an asymmetric dimer (protomers screw-transformed by 142°/4.1 Å), composed such that only one hormone could bind. This is compatible with the 1:2 asymmetry of negatively cooperative TSH:TSHR complexes and for the transactivation evident from functional complementation of binding-deficient and signaling-deficient GpHRs. By modeling, a symmetrized dimer can bind two hormones as in the 2:2 complexes that support TSHR switches in G-protein usage. Metazoans have evolved endocrine systems that signal through dimerized receptors in response to cognate hormones. These authors characterize a nematode homolog of such human receptors, presenting the cryo-EM structure of an asymmetric dimer that embodies properties of the human receptors.

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• A distinctive IGHV3-66 SARS-CoV-2 neutralizing antibody elicited by primary infection with an Omicron variant

  Structure · 2025-04-29 · 1 citations

  article1st authorCorresponding
  PublisherDOI

• NIEAs elicited by wild-type SARS-CoV-2 primary infection fail to enhance the infectivity of Omicron variants

  Virology Journal · 2025-02-24 · 1 citations

  articleOpen access

  SARS-CoV-2 infection widely induces antibody response targeting diverse viral proteins, including typical representative N-terminal domain (NTD), receptor-binding domain (RBD), and S2 subunit of spike. A lot of NTD-, RBD-, and S2-specific monoclonal antibodies (mAbs) have been isolated from COVID-19 convalescents, some of which displaying potent activities to inhibit viral infection. However, a small portion of NTD-specific mAbs elicited by wild-type (WT) SARS-CoV-2 primary infection could facilitate the virus entry into target cells in vitro, so called NTD-targeting infection-enhancing antibodies (NIEAs). To date, SARS-CoV-2 has evolved to massive variants carrying various NTD mutations, especially recent Omicron BA.2.86 and JN.1. In this study, we investigated whether these WT-NIEAs could still enhance the infectivity of emerging Omicron variants. Nine novel WT-NIEAs with diverse germline gene usage were identified from 3 individuals, effectively enlarging available antibody panel of NIEAs. Bivalent binding of NIEAs to inter-spike contributed to their infection-enhancing activities. WT-NIEAs could enhance the infectivity of SARS-CoV-2 variants emerged before Omicron, but ineffective to Omicron variants including BA.2.86 and JN.1, which was because of their changed antigenicity of NTDs. Overall, these data clearly demonstrated the cross-reactivity of these pre-existed WT-NIEAs to a series of SARS-CoV-2 variants, helping to evaluate the risk of enhanced infection of emerging variants in future. Additional 9 NIEAs were identified from individuals infected with wild-type SARS-CoV-2. This Fc-independent enhancement was mediated by the divalent binding of F(ab’)2 to NTDs. NIEAs could not enhance the infectivity of Omicron variants including BA.2.86 and JN.1. Changed antigenicity of Omicron variants led to the ineffectiveness of WT-induced NIEAs.

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• Structure and function of a pair of non-competing monoclonal antibodies against Langya henipavirus attachment glycoprotein

  Cell Reports · 2025-10-01 · 3 citations

  articleOpen access

  Langya henipavirus (LayV) is a zoonotic Parahenipavirus (Para-HNV) identified in recent years, discovered via surveillance of febrile patients with recent animal exposure in eastern China. The attachment glycoprotein (G) of HNV is critical for host cell entry and a key immune target. However, LayV-G exhibits notable antigenic differences from G of highly pathogenic bat-borne Hendra virus (HEV) and Nipah virus (NiV), implying vaccines or antibody therapies developed against HeV/NiV-G might be ineffective against LayV. Here, we immunize mice with LayV-G ectodomain and isolate a panel of LayV-G-targeting monoclonal antibodies (mAbs). We characterize two potent mAbs with pronounced crystallizable fragment (Fc)-mediated antiviral function and determine their cryo-electron microscopy (cryo-EM) structure binding to distinct epitopes of LayV-G head domain at a resolution of 2.92 Å, revealing antibody recognition mechanisms and potential conformational dynamics of LayV-G. Overall, our study defines two function-related epitopes of LayV-G, laying the foundation for therapeutic antibody development and vaccine design.

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• Structure of an LGR dimer – an evolutionary predecessor of glycoprotein hormone receptors

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-02 · 1 citations

  preprintOpen access

  Summary The glycoprotein hormones of humans, produced in the pituitary and acting through receptors in the gonads to support reproduction and in the thyroid gland for metabolism, have co-evolved from invertebrate counterparts 1,2 . These hormones are heterodimeric cystine-knot proteins; and their receptors bind the cognate hormone at an extracellular domain and transmit the signal of this binding through a transmembrane domain that interacts with a heterotrimeric G protein. Structures determined for the human receptors as isolated for cryogenic electron microscopy (cryo-EM) are all monomeric 3–6 despite compelling evidence for their functioning as dimers 7–10 . Here we describe the cryo-EM structure of the homologous receptor from a neuroendocrine pathway that promotes growth in a nematode 11 . This structure is an asymmetric dimer that can be activated by the hormone from that worm 12 , and it shares features especially like those of the thyroid stimulating hormone receptor (TSHR). When studied in the context of the human homologs, this dimer provides a structural explanation for the transactivation evident from functional complementation of binding-deficient and signaling-deficient receptors 7 , for the negative cooperativity in hormone action that is manifest in the 1:2 asymmetry of primary TSH:TSHR complexes 8,9 , and for switches in G-protein usage that occur as 2:2 complexes form 9,10 .

  PublisherDOI

• Fast Measurement of Output Capacitance of Fets

  SSRN Electronic Journal · 2025-01-01

  preprintOpen accessSenior author
  PublisherDOI

• SUN-211 L-Amino Acids Bind in the Calcium-Sensing Receptor's FlyTrap site but Signaling Responsiveness Depends upon Autocrine Competition

  Journal of the Endocrine Society · 2025-10-01

  articleOpen access

  Abstract Disclosure: A.D. Conigrave: None. M.A. Goolam: None. Q. Fan: None. D.T. Ward: None. S.J. Simpson: None. The calcium-sensing receptor (CaSR) is critical for calcium homeostasis by mediating calcium-stimulated inhibition of PTH secretion and promotion of renal calcium excretion. In a second major endocrine action, the CaSR is required for L-amino acid stimulated release of gastrointestinal hormones including GLP-1, GIP and PYY, with impacts on insulin release and postprandial blood glucose levels, and also energy intake. Amino acids (AAs) and calcium (Ca2+) interact mutually via linked CaSR binding sites to promote potency (AAs on Ca2+) and efficacy (Ca2+ on AAs), supporting interactions between calcium and amino acids upon the digestion of complex foods. Previous work has demonstrated that AAs robustly raise intracellular Ca2+ levels(1) and either stimulate (GLP-1, GIP, PYY (2)) or inhibit (PTH (3)) hormone secretion. Surprisingly, AAs have been reported to have no effect on accumulation of the inositol phosphate IP1 which, like Ca2+ mobilization, measures receptor-dependent activation of Gq/11 and PI-PLC. In the present study we hypothesized that autocrine production and release of local activators of the CaSR AA binding site might compete with exogenous AAs in static cell culture-based assays but not in assays in which cells are continuously perifused. In static cultures we found that washing cultured HEK-293 cells that were stably transfected with the CaSR with fresh AA-free medium markedly reduced Ca2+ sensitivity and exposed AA stimulation of IP1 accumulation. Since glutathione has been reported to stimulate the CaSR via the AA binding site(4), we also tested whether inhibition of glutathione synthesis with buthionine sulfoximine might expose AA stimulated IP1 accumulation. The effects of BSO treatment exceeded those of concerted washing.We conclude that the effects of AAs in CaSR expressing cells are dependent on the following factors: (i) Ca2+ concentration; (ii) AA concentration; (iii) local release of competing autocrine activators; (iv) the rate of exchange with systemic plasma. 1. Proc Natl Acad Sci USA. 2000;97:4814-92. J Physiol. 2012;590:2917-363. J Biol Chem. 2004;279:38151-94. J Biol Chem. 2011;286:8786-97 Presentation: Sunday, July 13, 2025

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Recent grants

• Mechanism of activation and modulation in human GABA(B) receptor

  NIH · $1.7M · 2018–2022

• Structural studies of human extracellular calcium-sensing receptor

  NIH · $1.3M · 2015–2020

• NIH Grant R01GM088454

  NIH · $1.6M · 2016

• Molecular mechanism of dimeric G protein-coupled receptor signaling

  NIH · $2.1M · 2021–2027

Frequent coauthors

• Zheng Zhang

  Shenzhen Third People’s Hospital

  118 shared

• Bin Ju

  84 shared

• Xiangyang Ge

  Shenzhen Third People’s Hospital

  60 shared

• Haiyan Wang

  53 shared

• Bing Zhou

  Institute of Zoology

  52 shared

• Lin Cheng

  University of Electronic Science and Technology of China

  45 shared

• Huimin Guo

  First Affiliated Hospital of Soochow University

  44 shared

• Shuo Song

  32 shared