Functional dynamics of G protein-coupled receptors reveal new routes for drug discovery

Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

Article  CAS  PubMed  Google Scholar 

Hauser, A. S., Attwood, M. M., Rask-Andersen, M., Schiöth, H. B. & Gloriam, D. E. Trends in GPCR drug discovery: new agents, targets and indications. Nat. Rev. Drug Discov. 16, 829–842 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Santos, R. et al. A comprehensive map of molecular drug targets. Nat. Rev. Drug Discov. 16, 19–34 (2017).

Article  CAS  PubMed  Google Scholar 

Sriram, K. & Insel, P. A. G protein-coupled receptors as targets for approved drugs: how many targets and how many drugs? Mol. Pharmacol. 93, 251–258 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wu, G. GPCR-targeting drugs: a renewed focus on a ubiquitous group of proteins. BioPharma Dive (7 March 2023).

Schmidt, C. Septerna: making another run on GPCRs. Nat. Biotechnol. https://doi.org/10.1038/d41587-023-00010-y (2023).

Summary of NDA approvals & receipts, 1938 to the present. US Food and Drug Administration (FDA) https://fda.gov/about-fda/histories-fda-regulated-products/summary-nda-approvals-receipts-1938-present (2023).

Kenakin, T. G-protein coupled receptors as allosteric machines. Recept. Channels 10, 51–60 (2004).

Article  CAS  PubMed  Google Scholar 

Latorraca, N. R., Venkatakrishnan, A. J. & Dror, R. O. GPCR dynamics: structures in motion. Chem. Rev. 117, 139–155 (2017).

Article  CAS  PubMed  Google Scholar 

Weis, W. I. & Kobilka, B. K. The molecular basis of G protein–coupled receptor activation. Annu. Rev. Biochem. 87, 897–919 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hilger, D., Masureel, M. & Kobilka, B. K. Structure and dynamics of GPCR signaling complexes. Nat. Struct. Mol. Biol. 25, 4–12 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gurevich, V. V. & Gurevich, E. V. Biased GPCR signaling: possible mechanisms and inherent limitations. Pharmacol. Ther. 211, 107540 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sutkeviciute, I. & Vilardaga, J.-P. Structural insights into emergent signaling modes of G protein-coupled receptors. J. Biol. Chem. 295, 11626–11642 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

García-Nafría, J. & Tate, C. G. Cryo-EM structures of GPCRs coupled to Gs, Gi and Go. Mol. Cell. Endocrinol. 488, 1–13 (2019).

Article  PubMed  Google Scholar 

Christopoulos, A. et al. International union of basic and clinical pharmacology. XC. Multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands. Pharmacol. Rev. 66, 918–947 (2014).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Chatzigoulas, A. & Cournia, Z. Rational design of allosteric modulators: challenges and successes. Wiley Interdiscip. Rev. Comput. Mol. Sci. 11, e1529 (2021).

Article  CAS  Google Scholar 

Ye, L., Van Eps, N., Zimmer, M., Ernst, O. P. & Prosser, R. S. Activation of the A2A adenosine G-protein-coupled receptor by conformational selection. Nature 533, 265–268 (2016).

Article  CAS  PubMed  Google Scholar 

Ye, L. et al. Mechanistic insights into allosteric regulation of the A2A adenosine G protein-coupled receptor by physiological cations. Nat. Commun. 9, 1372 (2018).

Article  PubMed  PubMed Central  Google Scholar 

Sušac, L., Eddy, M. T., Didenko, T., Stevens, R. C. & Wüthrich, K. A2A adenosine receptor functional states characterized by 19F-NMR. Proc. Natl Acad. Sci. USA 115, 12733–12738 (2018).

Article  PubMed  PubMed Central  Google Scholar 

Eddy, M. T. et al. Allosteric coupling of drug binding and intracellular signaling in the A2A adenosine receptor. Cell 172, 68–80.e12 (2018).

Article  CAS  PubMed  Google Scholar 

Huang, S. K. & Prosser, R. S. Dynamics and mechanistic underpinnings to pharmacology of class A GPCRs: an NMR perspective. Am. J. Physiol. Cell Physiol. 322, C739–C753 (2022).

Article  CAS  PubMed  Google Scholar 

Wei, S. et al. Single-molecule visualization of human A2A adenosine receptor activation by a G protein and constitutively activating mutations. Commun. Biol. 6, 1218 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wang, X., Neale, C., Kim, S.-K., Goddard, W. A. & Ye, L. Intermediate-state-trapped mutants pinpoint G protein-coupled receptor conformational allostery. Nat. Commun. 14, 1325 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Shimada, I., Ueda, T., Kofuku, Y., Eddy, M. T. & Wüthrich, K. GPCR drug discovery: integrating solution NMR data with crystal and cryo-EM structures. Nat. Rev. Drug Discov. 18, 59–82 (2019).

Article  CAS  PubMed  Google Scholar 

Huang, S. K. et al. Mapping the conformational landscape of the stimulatory heterotrimeric G protein. Nat. Struct. Mol. Biol. 30, 502–511 (2023).

Article  CAS  PubMed  Google Scholar 

Huang, S. K. et al. Delineating the conformational landscape of the adenosine A2A receptor during G protein coupling. Cell 184, 1884–1894.e14 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jones, A. J. Y. et al. Binding kinetics drive G protein subtype selectivity at the β1-adrenergic receptor. Nat. Commun. 15, 1334 (2024).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Solt, A. S. et al. Insight into partial agonism by observing multiple equilibria for ligand-bound and Gs-mimetic nanobody-bound β1-adrenergic receptor. Nat. Commun. 8, 1795 (2017).

Article  PubMed  PubMed Central  Google Scholar 

Isogai, S. et al. Backbone NMR reveals allosteric signal transduction networks in the β1-adrenergic receptor. Nature 530, 237–241 (2016).

Article  CAS  PubMed  Google Scholar 

Papasergi-Scott, M. M. et al. Time-resolved cryo-EM of G-protein activation by a GPCR. Nature 629, 1182–1191 (2024).

Article  CAS  PubMed  Google Scholar 

Manglik, A. et al. Structural insights into the dynamic process of β2-adrenergic receptor signaling. Cell 161, 1101–1111 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Calderón, J. C., Ibrahim, P., Gobbo, D., Gervasio, F. L. & Clark, T. General metadynamics protocol to simulate activation/deactivation of class a GPCRs: proof of principle for the serotonin receptor. J. Chem. Inf. Model. 63, 3105–3117 (2023).

Article  PubMed  Google Scholar 

Di Marino, D., Conflitti, P., Motta, S. & Limongelli, V. Structural basis of dimerization of chemokine receptors CCR5 and CXCR4. Nat. Commun. 14, 6439 (2023).

Article  PubMed

留言 (0)

沒有登入
gif