Illuminating The Druggable GPCR-OME

Contacts

• Bryan Roth’s lab: https://pdsp.unc.edu/rothlab/
• Brian Shoichet’s lab: https://www.bkslab.org/

Bryan Roth: @zenbrainestM
Roth Lab: @RothlabUNC

Overview

Collaborative work by Dr. Bryan Roth and Dr. Brian Shoichet focuses on illuminating the druggable GPCR-ome by two-pronged approach of empirical screening of drugs followed by computational screening against modeled structures of the GPCR to produced optimized lead compounds. Their work has led to discovery of molecule “ogerin” binding previously orphaned, GPR68. Additional collaborators include:

John Irwin, PhD (UCSF) – http://irwinlab.compbio.ucsf.edu/
Jian Jin, Ph.D. lab (MSSM) - https://labs.icahn.mssm.edu/jinlab/
Pablo Ariel, PhD from UNC Light Sheet Core - https://www.med.unc.edu/microscopy
Dale Cowley, PhD from UNC Mouse Genetics Core - https://www.med.unc.edu/amc/services/å

NIH grant number: 1U24 DK116195-01

Progress on IDG project as tracked by Protein Illumination Timeline:
GPCR Mice: https://druggablegenome.net/ProteinTimelineGPCRmice
GPCR Probes: https://druggablegenome.net/ProteinTimelineGPCRprobes

Expression images on A Mouse Imaging Server (AMIS):
Images of mouse expression of GPCR IDG proteins: http://amis.docking.org

DRGC-GPCR publications:

1. Kim Y, Gumpper RH, Liu Y, Kocak DD, Xiong Y, Cao C, Deng Z, Krumm BE, Jain M, Zhang S, Jin J, Roth BL. Bitter taste receptor activation by cholesterol and an intracellular tastant. Nature 2024. doi: 10.1038/s41586-024-07253-y Epub 2024 Apr 10. PMID: 38600377
2. Wang S, DeLeon C, Sun W, Quake SR, Roth BL, Südhof TC. Alternative splicing of latrophilin-3 controls synapse formation. Nature. 2024 Feb;626(7997):128-135. doi: 10.1038/s41586-023-06913-9. Epub 2024 Jan 17. PMID: 38233523; PMCID: PMC10830413.
3. Cao C, Roth BL. The structure, function, and pharmacology of MRGPRs. Trends Pharmacol Sci. 2023 Apr;44(4):237-251. doi: 10.1016/j.tips.2023.02.002. Epub 2023 Mar 2. PMID: 36870785; PMCID: PMC10066734.
4. Zhang S, Gumpper RH, Huang XP, Liu Y, Krumm BE, Cao C, Fay JF, Roth BL. Molecular basis for selective activation of DREADD-based chemogenetics. Nature. 2022 Dec;612(7939):354-362. doi: 10.1038/s41586-022-05489-0. Epub 2022 Nov 30. PMID: 36450989.
5. DiBerto JF, Olsen RHJ, Roth BL. TRUPATH: An Open-Source Biosensor Platform for Interrogating the GPCR Transducerome. Methods Mol Biol. 2022;2525:185-195. doi: 10.1007/978-1-0716-2473-9_13. PMID: 35836068.
6. Zhang S, Chen H, Zhang C, Yang Y, Popov P, Liu J, Krumm BE, Cao C, Kim K, Xiong Y, Katritch V, Shoichet BK, Jin J, Fay JF, Roth BL. Inactive and active state structures template selective tools for the human 5-HT_5A receptor. Nat Struct Mol Biol. 2022 Jul;29(7):677-687. doi: 10.1038/s41594-022-00796-6. Epub 2022 Jul 14. PMID: 35835867; PMCID: PMC9299520.
7. DiBerto JF, Smart K, Olsen RHJ, Roth BL. Agonist and antagonist TRUPATH assays for G protein-coupled receptors. STAR Protoc. 2022 Apr 1;3(2):101259. doi: 10.1016/j.xpro.2022.101259. PMID: 35403009; PMCID: PMC8983427.
8. Levit Kaplan A, Strachan RT, Braz JM, Craik V, Slocum S, Mangano T, Amabo V, O'Donnell H, Lak P, Basbaum AI, Roth BL, Shoichet BK. Structure-Based Design of a Chemical Probe Set for the 5-HT_5A Serotonin Receptor. J Med Chem. 2022 Mar 10;65(5):4201-4217. doi: 10.1021/acs.jmedchem.1c02031. Epub 2022 Feb 23. PMID: 35195401; PMCID: PMC9116900.
9. Cao C, Kang HJ, Singh I, Chen H, Zhang C, Ye W, Hayes BW, Liu J, Gumpper RH, Bender BJ, Slocum ST, Krumm BE, Lansu K, McCorvy JD, Kroeze WK, English JG, DiBerto JF, Olsen RHJ, Huang XP, Zhang S, Liu Y, Kim K, Karpiak J, Jan LY, Abraham SN, Jin J, Shoichet BK, Fay JF, Roth BL. Structure, function and pharmacology of human itch GPCRs. Nature. 2021 Dec;600(7887):170-175. doi: 10.1038/s41586-021-04126-6. Epub 2021 Nov 17. PMID: 34789874; PMCID: PMC9150435.
10. Nagai Y, Miyakawa N, Takuwa H, Hori Y, Oyama K, Ji B, Takahashi M, Huang XP, Slocum ST, DiBerto JF, Xiong Y, Urushihata T, Hirabayashi T, Fujimoto A, Mimura K, English JG, Liu J, Inoue KI, Kumata K, Seki C, Ono M, Shimojo M, Zhang MR, Tomita Y, Nakahara J, Suhara T, Takada M, Higuchi M, Jin J, Roth BL, Minamimoto T. Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys. Nat Neurosci. 2020 Sep;23(9):1157-1167. doi: 10.1038/s41593-020-0661-3. Epub 2020 Jul 6. PMID: 32632286.
11. Olsen RHJ, DiBerto JF, English JG, Glaudin AM, Krumm BE, Slocum ST, Che T, Gavin AC, McCorvy JD, Roth BL, Strachan RT. TRUPATH, an open-source biosensor platform for interrogating the GPCR transducerome. Nat Chem Biol. 2020 Aug;16(8):841-849. doi: 10.1038/s41589-020-0535-8. Epub 2020 May 4. PMID: 32367019; PMCID: PMC7648517.
12. Che T, English J, Krumm BE, Kim K, Pardon E, Olsen RHJ, Wang S, Zhang S, Diberto JF, Sciaky N, Carroll FI, Steyaert J, Wacker D, Roth BL. Nanobody- enabled monitoring of kappa opioid receptor states. Nat Commun. 2020 Mar 2;11(1):1145. doi: 10.1038/s41467-020-14889-7. PMID: 32123179; PMCID: PMC7052193.
13. Patel N, Huang XP, Grandner JM, Johansson LC, Stauch B, McCorvy JD, Liu Y, Roth B, Katritch V. Structure-based discovery of potent and selective melatonin receptor agonists. Elife. 2020 Mar 2;9:e53779. doi: 10.7554/eLife.53779. PMID: 32118583; PMCID: PMC7080406.
14. Stein RM, Kang HJ, McCorvy JD, Glatfelter GC, Jones AJ, Che T, Slocum S, Huang XP, Savych O, Moroz YS, Stauch B, Johansson LC, Cherezov V, Kenakin T, Irwin JJ, Shoichet BK, Roth BL, Dubocovich ML. Virtual discovery of melatonin receptor ligands to modulate circadian rhythms. Nature. 2020 Mar;579(7800):609-614. doi: 10.1038/s41586-020-2027-0. Epub 2020 Feb 10. PMID: 32040955; PMCID: PMC7134359.
15. English JG, Olsen RHJ, Lansu K, Patel M, White K, Cockrell AS, Singh D, Strachan RT, Wacker D, Roth BL. VEGAS as a Platform for Facile Directed Evolution in Mammalian Cells. Cell. 2019 Aug 8;178(4):1030. doi: 10.1016/j.cell.2019.07.036. Erratum for: Cell. 2019 Jul 25;178(3):748-761.e17. PMID: 31398329; PMCID: PMC6705592.
16. Yu X, Huang XP, Kenakin TP, Slocum ST, Chen X, Martini ML, Liu J, Jin J. Design, Synthesis, and Characterization of Ogerin-Based Positive Allosteric Modulators for G Protein-Coupled Receptor 68 (GPR68). J Med Chem. 2019 Aug 22;62(16):7557-7574. doi: 10.1021/acs.jmedchem.9b00869. Epub 2019 Aug 1. PMID: 31298539; PMCID: PMC6923801.
17. English JG, Olsen RHJ, Lansu K, Patel M, White K, Cockrell AS, Singh D, Strachan RT, Wacker D, Roth BL. VEGAS as a Platform for Facile Directed Evolution in Mammalian Cells. Cell. 2019 Jul 25;178(3):748-761.e17. doi: 10.1016/j.cell.2019.05.051. Epub 2019 Jul 4. Erratum in: Cell. 2019 Aug 8;178(4):1030. PMID: 31280962; PMCID: PMC6660416.
18. Roth BL. Molecular pharmacology of metabotropic receptors targeted by neuropsychiatric drugs. Nat Struct Mol Biol. 2019 Jul;26(7):535-544. doi: 10.1038/s41594-019-0252-8. Epub 2019 Jul 3. PMID: 31270468; PMCID: PMC6613815.
19. Stauch B, Johansson LC, McCorvy JD, Patel N, Han GW, Huang XP, Gati C, Batyuk A, Slocum ST, Ishchenko A, Brehm W, White TA, Michaelian N, Madsen C, Zhu L, Grant TD, Grandner JM, Shiriaeva A, Olsen RHJ, Tribo AR, Yous S, Stevens RC, Weierstall U, Katritch V, Roth BL, Liu W, Cherezov V. Publisher Correction: Structural basis of ligand recognition at the human MT₁ melatonin receptor. Nature. 2019 May;569(7756):E6. doi: 10.1038/s41586-019-1209-0. Erratum for: Nature. 2019 May;569(7755):284-288. PMID: 31048811.
20. Stauch B, Johansson LC, McCorvy JD, Patel N, Han GW, Huang XP, Gati C, Batyuk A, Slocum ST, Ishchenko A, Brehm W, White TA, Michaelian N, Madsen C, Zhu L, Grant TD, Grandner JM, Shiriaeva A, Olsen RHJ, Tribo AR, Yous S, Stevens RC, Weierstall U, Katritch V, Roth BL, Liu W, Cherezov V. Structural basis of ligand recognition at the human MT₁ melatonin receptor. Nature. 2019 May;569(7755):284-288. doi: 10.1038/s41586-019-1141-3. Epub 2019 Apr 24. Erratum in: Nature. 2019 May 3;: PMID: 31019306; PMCID: PMC6696938.
21. Johansson LC, Stauch B, McCorvy JD, Han GW, Patel N, Huang XP, Batyuk A, Gati C, Slocum ST, Li C, Grandner JM, Hao S, Olsen RHJ, Tribo AR, Zaare S, Zhu L, Zatsepin NA, Weierstall U, Yous S, Stevens RC, Liu W, Roth BL, Katritch V, Cherezov V. XFEL structures of the human MT₂ melatonin receptor reveal the basis of subtype selectivity. Nature. 2019 May;569(7755):289-292. doi: 10.1038/s41586-019-1144-0. Epub 2019 Apr 24. PMID: 31019305; PMCID: PMC6589158.
22. Shen Y, McCorvy JD, Martini ML, Rodriguiz RM, Pogorelov VM, Ward KM, Wetsel WC, Liu J, Roth BL, Jin J. D₂ Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine. J Med Chem. 2019 May 9;62(9):4755-4771. doi: 10.1021/acs.jmedchem.9b00508. Epub 2019 Apr 18. PMID: 30964661; PMCID: PMC6509010.
23. Martini ML, Liu J, Ray C, Yu X, Huang XP, Urs A, Urs N, McCorvy JD, Caron MG, Roth BL, Jin J. Defining Structure-Functional Selectivity Relationships (SFSR) for a Class of Non-Catechol Dopamine D₁ Receptor Agonists. J Med Chem. 2019 Apr 11;62(7):3753-3772. doi: 10.1021/acs.jmedchem.9b00351. Epub 2019 Mar 27. PMID: 30875219; PMCID: PMC6688508.
24. Thompson KJ, Khajehali E, Bradley SJ, Navarrete JS, Huang XP, Slocum S, Jin J, Liu J, Xiong Y, Olsen RHJ, Diberto JF, Boyt KM, Pina MM, Pati D, Molloy C, Bundgaard C, Sexton PM, Kash TL, Krashes MJ, Christopoulos A, Roth BL, Tobin AB. DREADD Agonist 21 Is an Effective Agonist for Muscarinic-Based DREADDs in Vitro and in Vivo. ACS Pharmacol Transl Sci. 2018 Sep 14;1(1):61-72. doi: 10.1021/acsptsci.8b00012. Epub 2018 Jul 27. PMID: 30868140; PMCID: PMC6407913.
25. Roth BL. How structure informs and transforms chemogenetics. Curr Opin Struct Biol. 2019 Aug;57:9-16. doi: 10.1016/j.sbi.2019.01.016. Epub 2019 Feb 25. PMID: 30818201.
26. Lyu J, Wang S, Balius TE, Singh I, Levit A, Moroz YS, O'Meara MJ, Che T, Algaa E, Tolmachova K, Tolmachev AA, Shoichet BK, Roth BL, Irwin JJ. Ultra-large library docking for discovering new chemotypes. Nature. 2019 Feb;566(7743):224-229. doi: 10.1038/s41586-019-0917-9. Epub 2019 Feb 6. PMID: 30728502; PMCID: PMC6383769.
27. Pellock SJ, Creekmore BC, Walton WG, Mehta N, Biernat KA, Cesmat AP, Ariyarathna Y, Dunn ZD, Li B, Jin J, James LI, Redinbo MR. Gut Microbial β-Glucuronidase Inhibition via Catalytic Cycle Interception. ACS Cent Sci. 2018 Jul 25;4(7):868-879. doi: 10.1021/acscentsci.8b00239. Epub 2018 Jul 12. PMID: 30062115; PMCID: PMC6062831.
28. Oprea TI, Bologa CG, Brunak S, Campbell A, Gan GN, Gaulton A, Gomez SM, Guha R, Hersey A, Holmes J, Jadhav A, Jensen LJ, Johnson GL, Karlson A, Leach AR, Ma'ayan A, Malovannaya A, Mani S, Mathias SL, McManus MT, Meehan TF, von Mering C, Muthas D, Nguyen DT, Overington JP, Papadatos G, Qin J, Reich C, Roth BL, Schürer SC, Simeonov A, Sklar LA, Southall N, Tomita S, Tudose I, Ursu O, Vidovic D, Waller A, Westergaard D, Yang JJ, Zahoránszky-Köhalmi G. Unexplored therapeutic opportunities in the human genome. Nat Rev Drug Discov. 2018 May;17(5):317-332. doi: 10.1038/nrd.2018.14. Epub 2018 Mar 23. Erratum in: Nat Rev Drug Discov. 2018 Mar 23;: PMID: 29472638; PMCID: PMC6339563.
29. McCorvy JD, Butler KV, Kelly B, Rechsteiner K, Karpiak J, Betz RM, Kormos BL, Shoichet BK, Dror RO, Jin J, Roth BL. Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs. Nat Chem Biol. 2018 Feb;14(2):126-134. doi: 10.1038/nchembio.2527. Epub 2017 Dec 11. PMID: 29227473; PMCID: PMC5771956.
30. Roth BL, Irwin JJ, Shoichet BK. Discovery of new GPCR ligands to illuminate new biology. Nat Chem Biol. 2017 Nov;13(11):1143-1151. doi: 10.1038/nchembio.2490. Epub 2017 Oct 18. PMID: 29045379; PMCID: PMC5835362.
31. Pera T, Deshpande DA, Ippolito M, Wang B, Gavrila A, Michael JV, Nayak AP, Tompkins E, Farrell E, Kroeze WK, Roth BL, Panettieri RA Jr, Benovic JL, An SS, Dulin NO, Penn RB. Biased signaling of the proton-sensing receptor OGR1 by benzodiazepines. FASEB J. 2018 Feb;32(2):862-874. doi: 10.1096/fj.201700555R. Epub 2018 Jan 4. PMID: 29042451; PMCID: PMC5888400.
32. Butler KV, MacDonald IA, Hathaway NA, Jin J. Report and Application of a Tool Compound Data Set. J Chem Inf Model. 2017 Nov 27;57(11):2699-2706. doi: 10.1021/acs.jcim.7b00343. Epub 2017 Nov 2. PMID: 29035535; PMCID: PMC5705340.
33. Wacker D, Stevens RC, Roth BL. How Ligands Illuminate GPCR Molecular Pharmacology. Cell. 2017 Jul 27;170(3):414-427. doi: 10.1016/j.cell.2017.07.009. PMID: 28753422; PMCID: PMC5560499.
34. Lansu K, Karpiak J, Liu J, Huang XP, McCorvy JD, Kroeze WK, Che T, Nagase H, Carroll FI, Jin J, Shoichet BK, Roth BL. In silico design of novel probes for the atypical opioid receptor MRGPRX2. Nat Chem Biol. 2017 May;13(5):529-536. doi: 10.1038/nchembio.2334. Epub 2017 Mar 13. PMID: 28288109; PMCID: PMC5391270.
35. Le Gonidec S, Chaves-Almagro C, Bai Y, Kang HJ, Smith A, Wanecq E, Huang XP, Prats H, Knibiehler B, Roth BL, Barak LS, Caron MG, Valet P, Audigier Y, Masri B. Protamine is an antagonist of apelin receptor, and its activity is reversed by heparin. FASEB J. 2017 Jun;31(6):2507-2519. doi: 10.1096/fj.201601074R. Epub 2017 Feb 27. PMID: 28242772; PMCID: PMC6191096.

Page reviewed on March 8, 2024