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How Ligands Illuminate GPCR Molecular Pharmacology
Open accessAbstract
G protein-coupled receptors (GPCRs), which are modulated by a variety of endogenous and synthetic ligands, represent the largest family of druggable targets in the human genome. Recent structural and molecular studies have both transformed and expanded classical concepts of receptor pharmacology and have begun to illuminate the distinct mechanisms by which structurally, chemically, and functionally diverse ligands modulate GPCR function. These molecular insights into ligand engagement and action have enabled new computational methods and accelerated the discovery of novel ligands and tool compounds, especially for understudied and orphan GPCRs. These advances promise to streamline the development of GPCR-targeted medications.
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“Slightly more than half of the non-olfactory GPCRs have annotated drugs and small molecules targeting them53,54,61; see also TABLE 1.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [53]
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“A recent analysis indicates, however, that a handful of GPCRs — mainly biogenic amine, muscarinic and opioid receptors — represent the most abundantly targeted receptors for FDA-approved medications53,54.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [53]
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“Alterations in GPCR signalling are implicated in the pathogenesis and treatment of neuropsychiatric55, immunological56, gastrointestinal57,58, cardiac59, renal, hormonal, infectious60 and many other disorders53,54.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [53]
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“GPCRs represent the largest family of druggable targets in the human genome9, with between 20% and 30% of approved drugs acting on them53,54.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [53]
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“GPCRs are membrane-bound, cell-surface receptors that transduce signals via interactions with heterotrimeric G proteins, arrestins and other cellular transducers53,54.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [53]
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“For covalent inhibitors, one of their chief advantages is potentially more durable inhibition at the PPI site leading to improved pharmacology in vivo [117, 118].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [118]
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“Forty-three percent of FDA-approved drugs target GPCRs, including opioid analgesics, antihistamines, antipsychotics, antimigraine drugs, and drugs against asthma and hypertension (Heukers et al., 2019; Wacker et al., 2017).”
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Advances in yeast synthetic biology for human G protein–coupled receptor biology and pharmacology
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“superfamily that engage the receptor from its intracellular side, directlypreventingGprotein coupling, oreven laterally fromwithin the cell membrane, freezing conformational rearrangements leading to accommodation of G proteins (32, 33).”
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“G protein-coupled receptors (GPCRs) constitute a protein family of receptors that sense molecules outside the cell and activate a number of different intracellular signal transduction pathways [72].”
BackgroundInsights into Repeated Renal Injury Using RNA-Seq with Two New RPTEC Cell Lines
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“…activated in this study since many GPCR ligands were likely elevated during injury that could include hormones, peptides, proteins such as chemokines, ions like Ca ++ , synaptic transmitters such as glutamine, and intermediary metabolites ranging from fatty acids, ATP, ADP, to many others [91].”
BackgroundResearch progress on the effects of opioids on the immune system
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Insights into the structure and activation mechanism of some class B1 GPCR family members
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A self-activating orphan receptor
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G-Protein Peptidomimetics Stabilize GPCR Active State Conformations
Gumpper, R. H., & Roth, B. L. (2021) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2021.03.009 · Cited by 6
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“As mentioned, functional [35S]GTPγS binding assays allow determination of drug efficacy [73].”
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“23,24 The plasticity of the β -AR system, 25,26 the ligand-directed signaling effect 25,26 as well as the lack of translationally reliable in vivo models (i.e., agonist vs antagonist vs inverse agonist in humans and rodents) are the main hurdles that contribute to make it highly difficult to…”
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“Based on efficacy, ligands are classified into four main types: full agonists, partial agonists, neutral antagonists, and inverse agonists (Kenakin 2002; Wacker et al. 2017).”
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“Additionally, studies by Wacker and coworkers [26,30] highlighted the role of binding site structural differences and amino acid sequence variations to achieve selective inhibition.”
BackgroundD1-like dopamine receptors promote B-cell differentiation in systemic lupus erythematosus
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“DRDs are members of the G protein-coupled receptors (GPCRs) family, which is the generic term for a class of membrane protein receptors that widely exist in various cells of the body, and GPCR often serves as a drug target [43, 44].”
BackgroundFluorescent tools for imaging class A G-protein coupled receptors
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“In general, the malleability of the reactiondiffusion processes involved in signaling is a way to overcome the relatively low variety in downstream pathways [5,6] and accurately reflect the complex abundance of potential stimuli.”
BackgroundGPR101 loss promotes insulin resistance and diet-induced obesity risk
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“Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability.”
Metadata
- Authors
- Wacker, D., Stevens, R. C., & Roth, B. L.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- University of Southern California (US)
- Corresponding author
- Roth, Bryan L.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 170
- Issue
- 3
- Pages
- 414-427
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5560499
- OpenAlex
- W2741191097
- Cited by
- 560
- References
- 115
- Citations by year
- 2026: 33 · 2025: 46 · 2024: 56 · 2023: 51 · 2022: 68 · 2021: 75 · 2020: 73 · 2019: 75 · 2018: 70 · 2017: 12
- FWCI
- 5.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institute of Health (RO1MH112205, UO1MH104974, U19MH82441, PO1DA035764)
- Michael Hooker Distinguished Professorship
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Keywords
- G protein-coupled receptors, GPCR pharmacology, ligand binding, ligand-receptor interactions, orphan G protein-coupled receptor, tool compounds, computational drug discovery, GPCR structure
- MeSH terms
- Animals, Humans, Ligands, Models, Molecular, Signal Transduction, Receptors, G-Protein-Coupled, Drug Discovery, Molecular Targeted Therapy
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