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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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“Introduction G protein–coupled receptors (GPCRs) are integral membrane proteins composed of seven transmembrane (TM)–spanning helices that are capable of binding to a diverse range of molecules outside of the cell to elicit a chemical response inside the cell (Wacker et al., 2017a).”
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“In contrast to agonists, neutral antagonists inhibit receptor signalling by occupying the agonist binding site, and inverse agonists shift the receptor conformational equilibrium towards more inactive-like states and, therefore, reduce basal signalling (Wacker et al., 2017).”
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“Increasing experimental evidence shows that the GPCR-signaling pathway is more complicated than classical signaling [11].”
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“For instance, agonists may be biased to different pathways, show drastically different efficacies or display different kinetics (Wacker et al., 2017).”
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“These molecules, which signal through GPCRs, have widespread effects in the brain, can also act on peripheral tissues, and are the targets of numerous pharmacological agents (28).”
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BackgroundInfluentialViral G Protein–Coupled Receptors Encoded by β- and γ-Herpesviruses
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“They transduce extracellular signals into the intracellular region, thereby controlling key physiological and pathophysiological effects within major areas such as the cardiovascular system, the musculoskeletal system, and the immune system as well as pain perception (9).”
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“The activation of GPCRs is achieved by a diverse range of ligands, including chemokines, lipids, vitamins, hormones, protein, peptides, and neurotransmitters [78].”
BackgroundVisualizing Ligand Binding to a GPCR In Vivo Using NanoBRET
Alcobia, D. C., Ziegler, A. I., Kondrashov, A. V., Comeo, E., Mistry, S. J., Kellam, B., Chang, A., Woolard, J., Hill, S. J., & Sloan, E. K. (2018) · iScience · doi:10.1016/j.isci.2018.08.006 · Cited by 34
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“Due to their physiological relevance, GPCRs represent promising targets for pharmacological treatment [10].”
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“This includes the introduction of mutations, which arrest proteins in a certain conformation [75]—an effect, which can also be achieved through the binding of ligands or antibody fragments [76,77]—deletions of parts of the proteins to eliminate”
BackgroundStructures of β1-adrenergic receptor in complex with Gs and ligands of different efficacies
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“Opioids exert their effect via opioid receptors, a member of a large superfamily of seven-transmembrane-spanning (7TM) G-protein-coupled receptors (GPCRs), mu (MOP receptor), kappa (KOP receptor), delta (DOP receptor), and nociceptin (NOP receptor) [10].”
Advancements in G protein‐coupled receptor biosensors to study GPCR‐G protein coupling
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“Most variants are predicated on a chimera with the original mini-Gαs subunit (Wan et al., 2018).”
BackgroundMethodInfluentialStudying GPCR conformational dynamics by single molecule fluorescence
Quast, R. B., & Margeat, E. (2019) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2019.110469 · Cited by 32
Duraisamy, K., Singh, K., Kumar, M., Lefranc, B., Bonnafé, E., Treilhou, M., Leprince, J., & Chow, B. (2021) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2021.04.040 · Cited by 30
Structure of GPR101–Gs enables identification of ligands with rejuvenating potential
Zhao, Y. C., Wang, J., Yang, F., Zhu, K., Wang, G., Guan, Y., Ning, S., Lü, Y., Li, Y., Zhang, C., et al. (2023) · Nature Chemical Biology · doi:10.1038/s41589-023-01456-6 · Cited by 30
“Moreover, such a side pocket could be a common characteristic of several constitutively activated GPCRs, which may provide a new avenue for the development of selective ligands targeting these orphan receptors.”
InfluentialMartini, M. L., Liu, J., Ray, C., Yu, X., Huang, X., Urs, A. N., Urs, N. M., McCorvy, J. D., Caron, M. G., Roth, B. L., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00351 · Cited by 28
Self-citationTRUPATH: An Open-Source Biosensor Platform for Interrogating the GPCR Transducerome
DiBerto, J. F., Olsen, R. H. J., & Roth, B. L. (2022) · Methods in molecular biology · doi:10.1007/978-1-0716-2473-9_13 · Cited by 30
Self-citation5-HT2A SNPs Alter the Pharmacological Signaling of Potentially Therapeutic Psychedelics
Schmitz, G. P., Jain, M. K., Slocum, S. T., & Roth, B. L. (2022) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.1c00815 · Cited by 29
Self-citationDasram, M. H., Walker, R. B., & Khamanga, S. M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113223 · Cited by 31
“Along with x-ray crystallography, and electron crystallography, electron paramagnetic resonance, ultraviolet absorbance, fluorescence and nuclear magnetic resonance (NMR) spectroscopy have facilitated the resolution of receptors at an atomic level [247] resulting in determination of the 3D structure of GPCR in additio…”
BackgroundCCR5: Established paradigms and new frontiers for a ‘celebrity’ chemokine receptor
Scurci, I., Martins, E., & Hartley, O. (2018) · Cytokine · doi:10.1016/j.cyto.2018.02.018 · Cited by 28
G-Protein Coupled Receptor Targeting on Myeloid Cells in Atherosclerosis
van der Vorst, E. P. C., Peters, L. J. F., Müller, M., Gencer, S., Yan, Y., Weber, C., & Döring, Y. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00531 · Cited by 29
GPCR signaling bias: an emerging framework for opioid drug development
Kise, R., & Inoue, A. (2024) · The Journal of Biochemistry · doi:10.1093/jb/mvae013 · Cited by 28
Molecular mechanisms of inverse agonism via κ-opioid receptor–G protein complexes
Tyson, A. S., Khan, S. U. R., Motiwala, Z., Han, G. W., Zhang, Z., Ranjbar, M., Styrpejko, D. J., Ramos‐Gonzalez, N., Woo, S., Villers, K., et al. (2025) · Nature Chemical Biology · doi:10.1038/s41589-024-01812-0 · Cited by 28
“True neutral antagonists are considered to be rare, as most ligands would likely modulate the equilibrium of receptor states to a certain extent 57 .”
Heteromerization of dopaminergic receptors in the brain: Pharmacological implications
Misganaw, D. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105600 · Cited by 29
Inactive and active state structures template selective tools for the human 5-HT5A receptor
Zhang, S., Chen, H., Zhang, C., Ying, Y., Popov, P. A., Liu, J., Krumm, B. E., Cao, C., Kim, K., Xiong, Y., et al. (2022) · Nature Structural & Molecular Biology · doi:10.1038/s41594-022-00796-6 · Cited by 26
Self-citationNox1 downregulators: A new class of therapeutics
Barton, M., Meyer, M. R., & Prossnitz, E. R. (2019) · Steroids · doi:10.1016/j.steroids.2019.108494 · Cited by 28
“The concept of unliganded, constitutively active G protein-coupled receptors, originally introduced by Costa and Herz in 1989 [64], is now firmly rooted in receptor pharmacology and occurs through the spontaneous population of active receptor states [65, 66].”
BackgroundNew light on cortical neuropeptides and synaptic network plasticity
Smith, S. J., Hawrylycz, M., Rossier, J., & Sümbül, U. (2020) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2020.04.002 · Cited by 26
Yuan, X., & Xu, Y. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19072105 · Cited by 28
“Due to the tremendous strides made in structure determination techniques, including NMR, X-ray crystallography, and Cryo-EM, the number of available 3D structures of GPCRs is increasing rapidly [72].”
BackgroundDoijen, J., Loy, T. V., Landuyt, B., Luyten, W. H. M. L., Schols, D., & Schoofs, L. (2019) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2019.04.041 · Cited by 29
Chemogenetics for cell-type-specific modulation of signalling and neuronal activity
Kang, H. J., Minamimoto, T., Wess, J., & Roth, B. L. (2023) · Nature Reviews Methods Primers · doi:10.1038/s43586-023-00276-1 · Cited by 27
Self-citationA Structural Understanding of Class B GPCR Selectivity and Activation Revealed
Krumm, B., & Roth, B. L. (2020) · Structure · doi:10.1016/j.str.2020.02.004 · Cited by 25
“Notably, the ‘‘kink’’ of TM6 allows the insertion of G protein.”
BackgroundInfluentialSelf-citationFunctional modulation of PTH1R activation and signaling by RAMP2
Nemec, K., Schihada, H., Kleinau, G., Zabel, U., Grushevskyi, E. O., Scheerer, P., Lohse, M. J., & Maiellaro, I. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2122037119 · Cited by 27
“The peptide ligands parathyroid hormone PTH (1-34) (human, H-4835-GMP, #4033364) and parathyroid hormone-related peptide (PTHrP) (1-34) (human, mouse, rat; #4017147) were from Bachem.”
Contributions of Noncanonical Smoothened Signaling During Embryonic Development
Pandit, T., & Ogden, S. K. (2017) · Journal of Developmental Biology · doi:10.3390/jdb5040011 · Cited by 25
Discovery of β-Arrestin Biased Ligands of 5-HT 7 R
Kim, Y., Kim, H., Lee, J., Lee, J. K., Min, S., Seong, J., Rhim, H., Tae, J., Lee, H. J., & Choo, H. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00642 · Cited by 26
Photoinduced receptor confinement drives ligand-independent GPCR signaling
Sánchez, M. F., Els‐Heindl, S., Beck‐Sickinger, A. G., Wieneke, R., & Tampé, R. (2021) · Science · doi:10.1126/science.abb7657 · Cited by 26
PRECOG: PREdicting COupling probabilities of G-protein coupled receptors
Singh, G., Inoue, A., Gutkind, J. S., Russell, R. B., & Raimondi, F. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz392 · Cited by 25
GPRC5b Modulates Inflammatory Response in Glomerular Diseases via NF-κB Pathway
Zambrano, S. S., Möller‐Hackbarth, K., Li, X., Rodriguez, P. Q., Charrin, E., Schwarz, A., Nystrom, J. C., Wernerson, A. Ö., Lal, M., & Patrakka, J. (2019) · Journal of the American Society of Nephrology · doi:10.1681/asn.2019010089 · Cited by 25
Detection of genome‐edited and endogenously expressed G protein‐coupled receptors
Soave, M., Stoddart, L. A., White, C. W., Kilpatrick, L. E., Goulding, J., Briddon, S. J., & Hill, S. J. (2021) · FEBS Journal · doi:10.1111/febs.15729 · Cited by 23
Yan, G., Zhang, G., Huang, J., Lan, Y., Sun, J., Zeng, C., Wang, Y., Qian, P., & He, L. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18112253 · Cited by 24
“In humans, GPCRs are involved in a lot of diseases and they are often the targets of many pharmaceutical drugs [43], and approximately 40% of all the modern medicinal drugs target GPCRs [44].”
BackgroundLee, J.-P., Zhang, R., Yan, M., Duggineni, S., Wakeman, D. R., Niles, W. L., Feng, Y., Chen, J. B., Hamblin, M. H., Han, E. B., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1911444117 · Cited by 24
“immune responses (22, 23), these receptors and their agonists are components of the regulatory axes for hematopoiesis and organogenesis in other systems (21, 24).”
InfluentialA guide to the design of synthetic gene networks in mammalian cells
Verbič, A., Praznik, A., & Jerala, R. (2020) · FEBS Journal · doi:10.1111/febs.15652 · Cited by 22
Inhibiting glycolysis rescues memory impairment in an intellectual disability Gdi1-null mouse
D’Adamo, P., Horvat, A., Gurgone, A., Mignogna, M. L., Bianchi, V., Masetti, M., Ripamonti, M., Taverna, S., Velebit, J., Malnar, M., et al. (2020) · Metabolism · doi:10.1016/j.metabol.2020.154463 · Cited by 25
Moal, E. L., Liu, Y., Collerette-Tremblay, J., Dumontier, S., Fabre, P., Molina, T., Dort, J., Orfi, Z., Denault, N., Boutin, J., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.abn8529 · Cited by 24
“G protein–coupled receptors (GPCRs) represent the largest family of drug-gable targets in the human genome ( 28 ).”
BackgroundGPCRs profiling and identification of GPR110 as a potential new target in HER2+ breast cancer
Bhat, R. R., Yadav, P., Sahay, D., Bhargava, D. K., Creighton, C. J., Yazdanfard, S., Al-Rawi, A., Yadav, V., Qin, L., Nanda, S., et al. (2018) · Breast Cancer Research and Treatment · doi:10.1007/s10549-018-4751-9 · Cited by 24
“The distinction between the classes of GPCRs implicated in tumorigenesis versus drug resistance may have implications for identifying potential endogenous GPCR ligands important in HER2+ BC biology in future studies [25, 26].”
Depletion of Gprc5a Promotes Development of Diabetic Nephropathy
Ma, X., Schwarz, A., Zambrano, S. S., Levin, A., Hultenby, K. R., Wernerson, A. M., Lal, M., & Patrakka, J. (2018) · Journal of the American Society of Nephrology · doi:10.1681/asn.2017101135 · Cited by 24
Peptide/Receptor Co-evolution Explains the Lipolytic Function of the Neuropeptide TLQP-21
Sahu, B. S., Rodriguez, P., Nguyen, M. E., Han, R., Cero, C., Razzoli, M., Piaggi, P., Laskowski, L. J., Pavličev, M., Muglia, L. J., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.07.101 · Cited by 24
“Importantly, GPCRs are associated with a large number of human diseases (Tschöp et al., 2016; Wacker et al., 2017), a finding that has stimulated, over the last several decades, increased interest in identifying their endogenous ligands and mechanism of activation as well as the development of pharmacological agonists…”
Background
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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