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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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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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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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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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Structure-guided development of heterodimer-selective GPCR ligands.

Harald Hübner1, Tamara Schellhorn1, Marie Gienger1

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Researchers designed novel bivalent ligands targeting dopamine D2 receptor/neurotensin NTS1 receptor (D2R/NTS1R) heterodimers. These ligands exhibit high affinity and selectivity, with a unique functional switch observed in co-expressing cells.

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Area of Science:

  • Pharmacology
  • Structural Biology
  • Medicinal Chemistry

Background:

  • G protein-coupled receptors (GPCRs) are crucial drug targets.
  • Crystal structures of GPCR ligand complexes enable rational drug design.
  • Understanding GPCR heterodimerization is key for developing selective therapeutics.

Purpose of the Study:

  • To design and synthesize novel bivalent ligands targeting D2R/NTS1R heterodimers.
  • To investigate the binding affinity, selectivity, and functional activity of these ligands.
  • To explore the potential of bivalent ligands for selective modulation of GPCR heterodimers.

Main Methods:

  • Structure-guided design of bivalent ligands.
  • Chemical synthesis of novel compounds.
  • Biological evaluation including binding assays, selectivity studies, and functional assays (cAMP, β-arrestin-2 recruitment).

Main Results:

  • Bivalent ligands with D2R pharmacophores and NTS1R agonist NT(8-13) were synthesized.
  • Compounds demonstrated picomolar binding affinity and high selectivity for D2R/NTS1R-coexpressing cells.
  • A functional switch was observed: inhibition of cAMP in D2R-expressing cells, stimulation in D2R/NTS1R-coexpressing cells.
  • Ligands induced strong, NTS1R-mediated β-arrestin-2 recruitment in co-expressing cells.

Conclusions:

  • Novel bivalent ligands targeting D2R/NTS1R heterodimers were successfully developed.
  • These ligands exhibit high affinity and unprecedented selectivity, offering a potential therapeutic advantage.
  • The observed functional switch and β-arrestin-2 recruitment highlight the potential for precise pharmacological control of GPCR heterodimers.