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Intracellular Receptor Modulation: Novel Approach to Target GPCRs
Natalia V Ortiz Zacarías1, Eelke B Lenselink1, Adriaan P IJzerman1
1Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
Trends in Pharmacological Sciences
|April 15, 2018
Summary
A conserved intracellular pocket in G protein-coupled receptors (GPCRs) offers a new target for drug development. Targeting this site provides novel pharmacological interventions for GPCRs.
Area of Science:
- Pharmacology
- Molecular Biology
- Structural Biology
Background:
- G protein-coupled receptors (GPCRs) are crucial drug targets.
- The intracellular region of GPCRs was traditionally viewed primarily as a signaling domain.
- Recent structural data revealed a conserved intracellular pocket across various GPCRs.
Purpose of the Study:
- To review the architecture and function of the GPCR intracellular region.
- To highlight the potential of a novel intracellular binding site for therapeutic modulation.
- To discuss strategies for targeting this intracellular pocket.
Main Methods:
- Review of recent crystal structures of GPCRs.
- Analysis of the conserved intracellular pocket and its overlap with known binding sites.
- Survey of existing literature on intracellular binding sites in chemokine receptors and other Class A GPCRs.
- Compilation of different targeting strategies: small molecules, pepducins, and nanobodies.
Main Results:
- A highly conserved intracellular pocket exists in multiple GPCRs.
- This pocket partially overlaps with the G protein and β-arrestin binding sites.
- Evidence supports the presence of such sites in chemokine receptors and other Class A GPCRs.
- Various therapeutic modalities, including small molecules, pepducins, and nanobodies, can target this site.
Conclusions:
- The intracellular pocket represents a novel and druggable site on GPCRs.
- Targeting this site offers a new paradigm for GPCR pharmacology, distinct from orthosteric modulation.
- Intracellular allosteric ligands may offer advantages over traditional orthosteric ligands for GPCR intervention.
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