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Related Concept Videos

G Protein-coupled Receptors01:15

G Protein-coupled Receptors

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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...
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Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

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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...
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Transducer Mechanism: G Protein–Coupled Receptors01:30

Transducer Mechanism: G Protein–Coupled Receptors

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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,...
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The Two-State Receptor Model01:29

The Two-State Receptor Model

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The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
The binding affinity of a drug determines its interaction with...
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Ligand Binding and Linkage00:49

Ligand Binding and Linkage

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Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
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Assembly of Signaling Complexes01:30

Assembly of Signaling Complexes

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Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
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Related Experiment Video

Updated: Sep 6, 2025

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

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AlphaFold2 versus experimental structures: evaluation on G protein-coupled receptors.

Xin-Heng He1,2, Chong-Zhao You1,2, Hua-Liang Jiang1,2,3,4

  • 1State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

Acta Pharmacologica Sinica
|July 1, 2022
PubMed
Summary
This summary is machine-generated.

AlphaFold2 can predict G protein-coupled receptor (GPCR) backbone features but has limitations. The predicted GPCR models differ from experimental structures, impacting drug design applications.

Keywords:
AlphaFold2G protein-coupled receptorsdrug designprotein structure predictionstructural biology

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Area of Science:

  • Structural Biology
  • Computational Biology
  • Pharmacology

Background:

  • G protein-coupled receptors (GPCRs) are crucial drug targets involved in numerous physiological processes.
  • Experimental determination of GPCR structures is challenging due to inherent instability.
  • AlphaFold2 is a recent AI tool for predicting protein structures, including GPCRs.

Purpose of the Study:

  • To evaluate the accuracy of G protein-coupled receptor (GPCR) structure models generated by AlphaFold2.
  • To assess the suitability of AlphaFold2-predicted GPCR models for functional studies and drug design.

Main Methods:

  • Comparison of AlphaFold2-predicted GPCR structures with experimentally determined structures.
  • Analysis of differences in extracellular and transmembrane domains, ligand-binding pockets, and transducer interfaces.

Main Results:

  • AlphaFold2 successfully captures the overall backbone topology of G protein-coupled receptors (GPCRs).
  • Significant discrepancies exist between predicted and experimental structures concerning domain assembly and interface conformations.
  • Ligand-binding pocket shapes in predicted models differ from those in experimental structures.

Conclusions:

  • While AlphaFold2 provides a useful starting point for GPCR structural analysis, its predictions have limitations.
  • The observed differences between predicted and experimental GPCR structures hinder direct application in structure-based drug design.
  • High-resolution experimental structural data remains essential for accurate functional studies and drug development targeting GPCRs.