Biochemistry Seminar: Qing R. Fan, "Structural mechanisms of ligand activation in dimeric GPCRs"

Wed, Sep 21, 2022 - 12:00 PM — Wed, Sep 21, 2022 - 01:00 PM
Admission Fee
Free. Coffee & tea will be available in the ASRC Cafe at 11:30 AM
Event Address
The speaker will be in-person:
ASRC Main Auditorium
85 Saint Nicholas Terrace
Current CUNY Cleared4 Pass is required for entrance; masks are optional.
Phone Number
Event Location
The seminar can also be viewed via Zoom.
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Event Details

Qing R. Fan, Associate Professor in Pharmacology and Pathology and Cell Biology at Columbia University Medical Center, will give a seminar on "Structural mechanisms of ligand activation in dimeric GPCRs."


Our research seeks to uncover the molecular mechanisms of activation and modulation of dimeric G protein-coupled receptors (GPCRs). GPCRs are distinguished by their seven-helix transmembrane domain which couples with specific G proteins to initiate downstream signaling cascades. They respond to a diverse array of external stimuli and constitute 30-50% of clinical drug targets.

GPCRs are divided into several classes. The class C family of GPCRs are unique in that they are obligate dimers and possess substantial extracellular domains. These receptors bind activating ligands remotely in the extracellular domain, which then transmits signals into and through the transmembrane domain for G protein activation. We are working to understand the activation mechanisms in two class C GPCR systems: human GABAB receptor and human calcium-sensing (CaS) receptor.

GABAB receptor functions as an obligatory heterodimer to mediate inhibitory neurotransmission. We determined the extracellular-domain structures of GABAB 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 ligand recognition and activation in GABAB receptor.

We recently solved a structure of near full-length GABAB receptor, captured in the inactive state by cryo-electron microscopy. Our structure revealed a novel heterodimer interface between the transmembrane domains of GABAB subunits. This interface embodies the signature of GABAB receptor’s inactive conformation. Furthermore, we identified a unique ¢intersubunit latch¢ motif within this transmembrane interface that maintains the inactive state of the receptor, since its disruption through mutations results in constitutive receptor activity. We also discovered multiple ligands pre-associated with the receptor, including a Ca2+ near the orthosteric agonist-binding site to upregulate receptor activity and two large endogenous phospholipids embedded within the TM domains to maintain receptor integrity.

CaS receptor functions as a homodimer to control extracellular Ca2+ homeostasis. We determined the extracellular-domain structures of human CaS receptor in the resting and active conformations. Our structures revealed novel binding sites for Ca2+, PO43-, and L-amino acids. Surprisingly, we discovered that L-amino acids are orthosteric agonists of CaS receptor, and act jointly with Ca2+ to trigger receptor activation. Additionally, PO43- mediates inhibition of CaS receptor activity.

We recently obtained the structures of a near-full length CaS receptor in three functional states, an inactive-state structure in the presence of a negative allosteric modulator, and two active-state structures in the absence and presence of a positive allosteric modulator. We found that CaS receptor activation involves a rearrangement of the transmembrane homodimer and formation of a novel dimer interface. In the inactive structure, direct transmembrane contact is absent. The critical development during receptor activation arises from a helix-breaking event that facilitates the formation of a transmembrane homodimer interface.

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