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Related Concept Videos

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

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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.
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G-protein Coupled Receptors01:21

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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.
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G Protein-coupled Receptors01:15

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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.
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GPCR Desensitization01:12

GPCR Desensitization

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G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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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
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Structure and function of a near fully-activated intermediate GPCR-Gαβγ complex.

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Researchers captured the structure of an intermediate G protein-coupled receptor (GPCR)-Gαβγ complex, revealing its role in initiating nucleotide exchange for drug development.

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Pharmacology

Background:

  • Understanding G protein-coupled receptor (GPCR) intermediate complexes is crucial for drug development.
  • Existing structural data predominantly shows fully activated GPCR-Gαβγ complexes, leaving intermediate states poorly understood.

Purpose of the Study:

  • To determine the structure of an intermediate GPCR-Gαsβγ complex.
  • To elucidate the functional role of this intermediate complex in GPCR signaling.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) at 2.6 Å resolution.
  • 19F quantitative NMR and molecular dynamics (MD) simulations to guide structural determination.
  • BODIPY-GDP/GTP based nucleotide exchange assays.

Main Results:

  • The structure of an intermediate GPCR-mini-Gαsβγ complex was determined by inhibiting its transition to the fully activated state.
  • Direct evidence shows this intermediate complex initiates a rate-limited nucleotide exchange.
  • The Gα subunit's α-helical domain is partially open, binding nucleotides at a non-canonical site.

Conclusions:

  • This study provides the first structural and functional insights into an intermediate GPCR-Gαsβγ complex.
  • The findings reveal a novel mechanism for nucleotide binding and exchange, bridging a gap in GPCR signaling knowledge.
  • This work has implications for the rational design of drugs targeting GPCR pathways.