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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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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

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.
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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.
GPCRs are also called heptahelical,...
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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 ligand-free GPCR-Gαβγ intermediate complex.

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Researchers revealed the structure of an intermediate G protein-coupled receptor (GPCR)-G protein complex. This intermediate complex initiates nucleotide exchange, offering new insights into GPCR signaling pathways.

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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-G protein complexes, leaving intermediate states poorly understood.

Purpose of the Study:

  • To determine the structure of an intermediate GPCR-G protein complex.
  • To investigate the functional role of this intermediate complex in initiating signaling.

Main Methods:

  • Utilized 19F quantitative NMR and molecular dynamics (MD) simulations to map conformational landscapes.
  • Employed cryo-electron microscopy (cryo-EM) to determine the structure of the intermediate complex at 2.8 Å resolution.
  • Blocked the transition to the fully activated state to capture the intermediate.

Main Results:

  • Determined the cryo-EM structure of an intermediate GPCR-mini-Gαsβγ complex.
  • Provided direct evidence that the intermediate complex drives a rate-limited nucleotide exchange.
  • Observed partial opening of the Gα's α-helical domain (AHD) engaged by a second nucleotide, supported by MD simulations.

Conclusions:

  • The intermediate complex represents a distinct functional state in GPCR signaling.
  • This intermediate complex can initiate nucleotide exchange independently of full activation.
  • These findings bridge a critical knowledge gap in GPCR signaling mechanisms and drug discovery.