Related Experiment Video

Updated: May 15, 2026

Visualizing the Conformational Dynamics of Membrane Receptors Using Single-Molecule FRET
10:59

Visualizing the Conformational Dynamics of Membrane Receptors Using Single-Molecule FRET

Published on: August 17, 2022

Conformational ensemble view of G protein-coupled receptors and the effect of mutations and ligand binding

Ravinder Abrol1, Soo-Kyung Kim, Jenelle K Bray

  • 1Materials and Process Simulation Center, California Institute of Technology, Pasadena, California, USA. abrol@wag.caltech.edu

Methods in Enzymology
|January 22, 2013
PubMed

Insights

G protein-coupled receptors (GPCRs) exhibit structural flexibility, adopting multiple conformations that dictate distinct cellular signaling pathways. Understanding these receptor conformations is key to unlocking functional selectivity and targeted therapies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • G protein-coupled receptors (GPCRs) are crucial membrane proteins translating extracellular signals into intracellular responses.
  • GPCR pleiotropy arises from structural flexibility, allowing access to multiple conformations.
  • Each conformation can potentially activate distinct intracellular signaling cascades.

Purpose of the Study:

  • To explore the ensemble of conformations characterizing the full thermodynamic landscape of GPCRs.
  • To investigate how mutations and ligand binding modulate the GPCR energy landscape.
  • To provide testable hypotheses on the structural basis of GPCR activation and functional selectivity.

Main Methods:

  • Utilizing computational methods to predict the ensemble of GPCR conformations.
  • Analyzing structural data from crystallized GPCRs.
  • Investigating the effects of mutations and ligand interactions on receptor conformations.

Main Results:

  • Computational approaches can predict a broader range of GPCR conformations than experimental methods alone.
  • Mutations and ligand binding can stabilize specific GPCR conformations.
  • Stabilized conformations correlate with specific downstream physiological functions.

Conclusions:

  • The conformational ensemble of GPCRs is central to their functional diversity.
  • Modulating the GPCR energy landscape offers a route to achieving functional selectivity.
  • This research provides a structural framework for understanding GPCR activation and drug design.

More Related Videos

G Protein-selective GPCR Conformations Measured Using FRET Sensors in a Live Cell Suspension Fluorometer Assay09:12

G Protein-selective GPCR Conformations Measured Using FRET Sensors in a Live Cell Suspension Fluorometer Assay

Published on: September 10, 2016

Modeling Ligands into Maps Derived from Electron Cryomicroscopy09:30

Modeling Ligands into Maps Derived from Electron Cryomicroscopy

Published on: July 19, 2024

Related Concept Videos

G Protein-coupled Receptors01:15

G Protein-coupled Receptors

G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
G Protein-coupled Receptors01:15

G Protein-coupled Receptors

G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
Transducer Mechanism: G Protein–Coupled Receptors01:30

Transducer Mechanism: G Protein–Coupled Receptors

G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
GPCRs are also called heptahelical, 7TM, or...
Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high affinity and are together...
G-protein Coupled Receptors01:21

G-protein Coupled Receptors

G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
G-protein Coupled Receptors01:21

G-protein Coupled Receptors

G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.