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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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“Furthermore, the same ligand can activate different GPCR subtypes, which sometimes mediate opposite cellular outcomes (Wheatley et al., 2012; Wacker et al., 2017).”
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“In addition, numerous Food and Drug Administration (FDA)-approved drugs target G-protein-coupled receptors (GPCRs) [33], and designer receptors exclusively activated by designer drugs (DREADDs), which are tools for chemogenetics, are modified GPCRs.”
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“Activation of plasma membrane GPCRs usually is mediated by the binding of an agonist that stabilizes the active conformation of the receptor with the subsequent recruitment and activation of intracellular signaling pathways [20].”
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“G protein-coupled receptors (GPCRs) are among the most widely studied pharmacological targets [1,2].”
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BackgroundIlluminating the understudied GPCR-ome
Majumdar, S., Chiu, Y.-T., Pickett, J. E., & Roth, B. L. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103848 · Cited by 15
Self-citationAdhikary, K., Banerjee, P., Barman, S., Banerjee, A., Sarkar, A., Bag, S., Chatterjee, S., Bandyopadhyay, B., & Panja, A. S. (2024) · Acta Tropica · doi:10.1016/j.actatropica.2024.107356 · Cited by 15
Positive allosteric modulation of a GPCR ternary complex
Burger, W. A. C., Draper-Joyce, C. J., Valant, C., Christopoulos, A., & Thal, D. M. (2024) · Science Advances · doi:10.1126/sciadv.adp7040 · Cited by 15
“G protein–coupled receptors (GPCRs) are cell surface proteins activated by extracellular environmental stimuli and, in response, facilitate the modulation of intracellular signaling pathways and biological responses ( 1 ).”
BackgroundSarkar, P., Rao, B. D., & Chattopadhyay, A. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00499 · Cited by 15
Paprocki, J. D., Biener, G., Stoneman, M. R., & Raicu, V. (2020) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.0c06081 · Cited by 15
An, X., Bai, Q., Bing, Z., Zhou, S., Shi, D., Liu, H., & Yao, X. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00535 · Cited by 15
Kim, D., Park, J. C., & Lee, J. (2022) · Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology · doi:10.1016/j.cbpc.2022.109297 · Cited by 15
Tzortzini, E., Corey, R. A., & Kolocouris, A. (2023) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.2c01181 · Cited by 14
Asama, R., Liu, C. J. S., Tominaga, M., Cheng, Y.-R., Nakamura, Y., Kondo, A., Wang, H.-Y. A., & Ishii, J. (2024) · Microbial Cell Factories · doi:10.1186/s12934-024-02379-0 · Cited by 14
“They respond to diverse external stimuli, including light, small compounds, and peptides, and transduce the signal via coupling with a guanine nucleotide-binding protein (G-protein), to regulate a complex variety of cellular functions [14, 15].”
BackgroundMolecular glues as potential GPCR therapeutics
Roth, B. L., & Krumm, B. E. (2024) · Biochemical Pharmacology · doi:10.1016/j.bcp.2024.116402 · Cited by 14
Self-citationTian, L., Qiang, T., Liu, S., Zhang, B., Zhang, Y., Zhang, B., Hu, J., Zhang, J., Qi, L., Ke, C., et al. (2025) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2025.108795 · Cited by 14
Oxytocin/vasopressin-like neuropeptide signaling in insects
Muratspahić, E., Monjon, E., Duerrauer, L., Rogers, S. M., Cullen, D. A., Broeck, J. V., & Gruber, C. W. (2020) · Vitamins and hormones · doi:10.1016/bs.vh.2019.08.011 · Cited by 15
Marino, J., & Schertler, G. F. X. (2021) · Journal of Structural Biology · doi:10.1016/j.jsb.2021.107699 · Cited by 15
Kim, D., Kim, M., Hagiwara, A., & Lee, J. (2021) · Comparative Biochemistry and Physiology Part D Genomics and Proteomics · doi:10.1016/j.cbd.2021.100861 · Cited by 14
Schmitz, G. P., Chiu, Y.-T., König, G. M., Kostenis, E., Roth, B. L., & Herman, M. A. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.11.15.516655 · Cited by 16
Self-citationA general method for chemogenetic control of peptide function
Shen, J., Geng, L., Li, X., Emery, C., Kroning, K. E., Shingles, G., Lee, K. L., Heyden, M., Li, P., & Wang, W. (2022) · Nature Methods · doi:10.1038/s41592-022-01697-8 · Cited by 13
G protein-coupled receptors as targets for transformative neuropsychiatric therapeutics
Schmitz, G. P., & Roth, B. L. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00397.2022 · Cited by 13
Self-citationProtons taken hostage: Dynamic H-bond networks of the pH-sensing GPR68
Kapur, B. M., Baldessari, F., Lazaratos, M., Nar, H., Schnapp, G., Giorgetti, A., & Bondar, A. (2023) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2023.08.034 · Cited by 13
“GPCRs are integral membrane proteins localized in cell membranes where they sense external messengers such as light, neurotransmitters, drugs, or protons, triggering downstream signaling pathways that elicit a specific cellular response [2,3].”
BackgroundNatural Product-Based Drug Designing for Treatment of Human Parasitic Diseases
Ahmad, S., Kishan, A., Chitkara, P., Asiri, S. A., Eswaran, M., Mehta, S., & Alam, M. (2023) · Springer eBooks · doi:10.1007/978-981-19-9605-4_3 · Cited by 13
Exploring structure-based drug discovery of GPCRs beyond the orthosteric binding site
Chen, Z., Ren, X., Zhou, Y., & Huang, N. (2024) · hLife · doi:10.1016/j.hlife.2024.01.002 · Cited by 14
“An antagonist, on the other hand, has no activity in the absence of an agonist or inverse agonist but can block the activity of either [5,6].”
Bertalan, É., Rodrigues, M. J., Schertler, G. F. X., & Bondar, A. (2024) · British Journal of Pharmacology · doi:10.1111/bph.16387 · Cited by 13
“Humans have >800 GPCR sequences (Fredriksson et al., 2003), with specialized GPCRs responsible for mediating cellular responses to diverse extracellular stimuli, such as photons, protons and other ions, odorant molecules, hormones, neurotransmitters and proteins (Wacker et al., 2017).”
Optogenetic Techniques for Manipulating and Sensing G Protein-Coupled Receptor Signaling
Abreu, N., & Levitz, J. (2020) · Methods in molecular biology · doi:10.1007/978-1-0716-0755-8_2 · Cited by 16
Strategies for targeting cell surface proteins using multivalent conjugates and chemical biology
Sachdev, S., Cabalteja, C. C., & Cheloha, R. W. (2021) · Methods in cell biology · doi:10.1016/bs.mcb.2021.06.004 · Cited by 12
The sugar daddy: the role of the renal proximal tubule in glucose homeostasis
Hotait, Z. S., Cascio, J. N. L., Choos, E. N. D., & Shepard, B. D. (2022) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00225.2022 · Cited by 13
12‐HETE/GPR31 induces endothelial dysfunction in diabetic retinopathy
Chen, S., Qin, X., Sun, Y., Ma, Z., Niu, C., Xu, Y., Lu, L., & Zou, H. (2024) · The FASEB Journal · doi:10.1096/fj.202401362r · Cited by 12
“38,39 Therefore, GPR31 is a potential drug target that is more translatable than enzymes.”
Katayama, K., Suzuki, K., Suno, R., Kise, R., Tsujimoto, H., Iwata, S., Inoue, A., Kobayashi, T., & Kandori, H. (2021) · Communications Biology · doi:10.1038/s42003-021-02836-1 · Cited by 12
Ferré, G., Anazia, K., Silva, L. O., Thakur, N., Ray, A. P., & Eddy, M. T. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111844 · Cited by 12
Munguba, H., Srivastava, I., Gutzeit, V. A., Singh, A., Vijay, A., Kristt, M., Arefin, A., Thukral, S., Broichhagen, J., Stujenske, J. M., et al. (2024) · Neuron · doi:10.1016/j.neuron.2025.01.002 · Cited by 13
Genetics‐Based Targeting Strategies for Precise Neuromodulation
He, Y., Wei, Z., Xu, J., Jin, F., Li, T., Qian, L., Ma, J., Zheng, W., Javanmardi, N., Wang, T., et al. (2025) · Advanced Science · doi:10.1002/advs.202413817 · Cited by 13
Shalaeva, D. N., Cherepanov, D. A., Galperin, M. Y., Vriend, G., & Mulkidjanian, A. Y. (2019) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2019.183051 · Cited by 10
Misawa, K., Mima, M., Yamada, S., Imai, A., Mochizuki, D., Ishikawa, R., Kita, J., Yamaguchi, Y., Endo, S., Misawa, Y., et al. (2020) · Journal of Translational Medicine · doi:10.1186/s12967-020-02214-1 · Cited by 12
Vibrational analysis of acetylcholine binding to the M 2 receptor
Suzuki, K., Katayama, K., Sumii, Y., Nakagita, T., Suno, R., Tsujimoto, H., Iwata, S., Kobayashi, T., Shibata, N., & Kandori, H. (2021) · RSC Advances · doi:10.1039/d1ra01030a · Cited by 12
The Sniffing Kidney: Roles for Renal Olfactory Receptors in Health and Disease
Shepard, B. D. (2021) · Kidney360 · doi:10.34067/kid.0000712021 · Cited by 12
Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile
Rimbert, A., Yeung, M. W., Dalila, N., Thio, C. H. L., Yu, H., Loaiza, N., Oldoni, F., van der Graaf, A., Wang, S., Said, M. A., et al. (2022) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.122.317514 · Cited by 12
The Pursuit of Enzyme Activation: A Snapshot of the Gold Rush
Teng, M., Young, D. W., & Tan, Z. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01291 · Cited by 12
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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