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Related Concept Videos

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 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

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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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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...
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Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
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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.
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Related Experiment Video

Updated: Aug 10, 2025

Parallel Interrogation of β-Arrestin2 Recruitment for Ligand Screening on a GPCR-Wide Scale using PRESTO-Tango Assay
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Structural basis of efficacy-driven ligand selectivity at GPCRs.

Alexander S Powers1,2,3,4,5, Vi Pham6, Wessel A C Burger6,7

  • 1Department of Chemistry, Stanford University, Stanford, CA, USA.

Nature Chemical Biology
|February 13, 2023
PubMed
Summary

Achieving drug selectivity between similar receptors is difficult. This study reveals the molecular mechanism behind efficacy-driven selectivity using xanomeline and muscarinic acetylcholine receptors (mAChRs), enabling rational drug design.

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Computational Chemistry

Background:

  • Drug selectivity is crucial for therapeutic efficacy, yet challenging to achieve between closely related receptors.
  • Efficacy-driven selectivity, where ligands preferentially activate certain receptors despite similar binding affinities, offers a potential solution but lacks a clear molecular mechanism.
  • Understanding this mechanism is vital for designing novel therapeutics targeting G-protein-coupled receptors (GPCRs).

Purpose of the Study:

  • To elucidate the structural basis of efficacy-driven selectivity for xanomeline between muscarinic acetylcholine receptors (mAChRs).
  • To experimentally validate the proposed mechanism.
  • To guide the rational design of new ligands with tailored selectivity profiles.

Main Methods:

  • All-atom molecular dynamics simulations to model ligand-receptor interactions.
  • Biochemical assays to validate simulation findings and assess receptor activation.
  • Structure-based drug design to create novel ligands with modified selectivity.

Main Results:

  • Xanomeline exhibits similar binding modes in inactive mAChRs but distinct interactions in active states.
  • These differences in active-state binding lead to divergent effects on receptor stability, explaining efficacy-driven selectivity.
  • Experimental validation confirmed the simulation-derived mechanism, and newly designed ligands demonstrated altered selectivity profiles.

Conclusions:

  • The study reveals the atomic-level mechanism underlying efficacy-driven selectivity in mAChRs.
  • This understanding facilitates the rational design of selective ligands for pharmaceutically important GPCRs.
  • The findings provide a framework for developing safer and more effective drugs by enhancing target selectivity.