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Related Concept Videos

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...
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GPCRs Regulate Adenylyl Cylase Activity

Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of cells.
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Small GTPases - Ras and Rho01:24

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Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
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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.
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G Protein-coupled Receptors01:15

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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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Elevated conformational dynamics makes ACKR3 activation-prone and G protein-incompetent.

Kai Wang1, Tony Ngo1,2, Ekta Khare1,3

  • 1Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, 92093, USA.

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The atypical receptor ACKR3 exhibits unique dynamics, leading to its high activation propensity and promiscuous ligand binding, unlike the canonical CXCR4 receptor. These distinct conformational dynamics govern ACKR3

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Chemokine receptors like CXCR4 and atypical receptors like ACKR3 mediate cell migration via CXCL12.
  • CXCR4 signals through G proteins and β-arrestins, while ACKR3 is G protein-uncoupled and β-arrestin-biased.
  • Differences in activation mechanisms and ligand sensitivity suggest distinct receptor dynamics between ACKR3 and CXCR4.

Purpose of the Study:

  • To investigate the molecular basis for the distinct activation dynamics of ACKR3 and CXCR4.
  • To compare the conformational changes of ACKR3 and CXCR4 upon ligand binding using molecular dynamics simulations.

Main Methods:

  • Atomistic molecular dynamics (MD) simulations of ACKR3 and CXCR4 complexes with CXCL12 variants (WT and [P2G]).
  • Analysis of transmembrane (TM) helix dynamics and residue interaction networks.
  • Validation using Bioluminescence Resonance Energy Transfer (BRET)-based assays with receptor mutants.

Main Results:

  • CXCR4 adopts a stable active state with WT CXCL12 but an inactive state with [P2G]CXCL12.
  • ACKR3 displays variable TM6 and persistently active TM7 states with both WT and [P2G]CXCL12, retaining agonistic activity.
  • Ligand-mediated networks regulating TM6/TM7 activation in CXCR4 are absent/disrupted in ACKR3, allowing less constrained dynamics.

Conclusions:

  • ACKR3's unique conformational dynamics drive its activation propensity and ligand promiscuity.
  • Distinct dynamics and disrupted interaction networks explain ACKR3's atypical signaling compared to CXCR4.
  • These findings elucidate the structural basis for ACKR3's function in chemokine signaling.