Structure, function and pharmacology of human itch GPCRs

Can Cao; Hye Jin Kang; Isha Singh; He Chen; Chengwei Zhang; Wenlei Ye; Byron W. Hayes; Jing Liu; Ryan H. Gumpper; Brian J. Bender; Samuel T. Slocum; Brian E. Krumm; Katherine Lansu; John D. McCorvy; Wesley K. Kroeze; Justin G. English; Jeffrey F. DiBerto; Reid H.J. Olsen; Xi Ping Huang; Shicheng Zhang; Yongfeng Liu; Kuglae Kim; Joel Karpiak; Lily Y. Jan; Soman N. Abraham; Jian Jin; Brian K. Shoichet; Jonathan F. Fay; Bryan L. Roth

doi:10.1038/s41586-021-04126-6

Structure, function and pharmacology of human itch GPCRs

Can Cao, Hye Jin Kang, Isha Singh, He Chen, Chengwei Zhang, Wenlei Ye, Byron W. Hayes, Jing Liu, Ryan H. Gumpper, Brian J. Bender, Samuel T. Slocum, Brian E. Krumm, Katherine Lansu, John D. McCorvy, Wesley K. Kroeze, Justin G. English, Jeffrey F. DiBerto, Reid H.J. Olsen, Xi Ping Huang, Shicheng ZhangYongfeng Liu, Kuglae Kim, Joel Karpiak, Lily Y. Jan, Soman N. Abraham, Jian Jin, Brian K. Shoichet, Jonathan F. Fay, Bryan L. Roth

Department of Pharmacy

Research output: Contribution to journal › Article › peer-review

68 Citations (Scopus)

Abstract

The MRGPRX family of receptors (MRGPRX1–4) is a family of mas-related G-protein-coupled receptors that have evolved relatively recently¹. Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast cell-mediated hypersensitivity reactions^2–5. MRGPRX2 couples to both G_i and G_q in mast cells⁶. Here we describe agonist-stabilized structures of MRGPRX2 coupled to G_i1 and G_q in ternary complexes with the endogenous peptide cortistatin-14 and with a synthetic agonist probe, respectively, and the development of potent antagonist probes for MRGPRX2. We also describe a specific MRGPRX4 agonist and the structure of this agonist in a complex with MRGPRX4 and G_q. Together, these findings should accelerate the structure-guided discovery of therapeutic agents for pain, itch and mast cell-mediated hypersensitivity.

Original language	English
Pages (from-to)	170-175
Number of pages	6
Journal	Nature
Volume	600
Issue number	7887
DOIs	https://doi.org/10.1038/s41586-021-04126-6
Publication status	Published - 2021 Dec 2

Bibliographical note

Funding Information:
Acknowledgements This work was supported by NIH grants U24DA116195 (to B.L.R., B.K.S. and J.J.) and R35GM122481 (to B.K.S.), and by the Michael Hooker Distinguished Professorship to B.L.R. and NIH grant R01-DK121969, R01-DK121032 and R56-AI139620 to S.N.A. We thank J. Peck and J. Strauss of the UNC Cryo-EM Core Facility for technical assistance in this project. W.Y. is partly supported by Program for Breakthrough Biomedical Research funded by the Sandler Foundation, University of California, San Francisco. L.Y.J. is a Howard Hughes Medical Institute investigator. We thank S.-L. Shyng for the plasmids encoding human Kir6.2 and SUR1. The Titan X Pascal used for this research was kindly donated to J.F.F. by the NVIDIA Corporation.

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© 2021, The Author(s), under exclusive licence to Springer Nature Limited.

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Cao, C., Kang, H. J., Singh, I., Chen, H., Zhang, C., Ye, W., Hayes, B. W., Liu, J., Gumpper, R. H., Bender, B. J., Slocum, S. T., Krumm, B. E., Lansu, K., McCorvy, J. D., Kroeze, W. K., English, J. G., DiBerto, J. F., Olsen, R. H. J., Huang, X. P., ... Roth, B. L. (2021). Structure, function and pharmacology of human itch GPCRs. Nature, 600(7887), 170-175. https://doi.org/10.1038/s41586-021-04126-6

@article{62d2091e9739464184506d55c9a01983,

title = "Structure, function and pharmacology of human itch GPCRs",

abstract = "The MRGPRX family of receptors (MRGPRX1–4) is a family of mas-related G-protein-coupled receptors that have evolved relatively recently1. Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast cell-mediated hypersensitivity reactions2–5. MRGPRX2 couples to both Gi and Gq in mast cells6. Here we describe agonist-stabilized structures of MRGPRX2 coupled to Gi1 and Gq in ternary complexes with the endogenous peptide cortistatin-14 and with a synthetic agonist probe, respectively, and the development of potent antagonist probes for MRGPRX2. We also describe a specific MRGPRX4 agonist and the structure of this agonist in a complex with MRGPRX4 and Gq. Together, these findings should accelerate the structure-guided discovery of therapeutic agents for pain, itch and mast cell-mediated hypersensitivity.",

author = "Can Cao and Kang, {Hye Jin} and Isha Singh and He Chen and Chengwei Zhang and Wenlei Ye and Hayes, {Byron W.} and Jing Liu and Gumpper, {Ryan H.} and Bender, {Brian J.} and Slocum, {Samuel T.} and Krumm, {Brian E.} and Katherine Lansu and McCorvy, {John D.} and Kroeze, {Wesley K.} and English, {Justin G.} and DiBerto, {Jeffrey F.} and Olsen, {Reid H.J.} and Huang, {Xi Ping} and Shicheng Zhang and Yongfeng Liu and Kuglae Kim and Joel Karpiak and Jan, {Lily Y.} and Abraham, {Soman N.} and Jian Jin and Shoichet, {Brian K.} and Fay, {Jonathan F.} and Roth, {Bryan L.}",

note = "Funding Information: Acknowledgements This work was supported by NIH grants U24DA116195 (to B.L.R., B.K.S. and J.J.) and R35GM122481 (to B.K.S.), and by the Michael Hooker Distinguished Professorship to B.L.R. and NIH grant R01-DK121969, R01-DK121032 and R56-AI139620 to S.N.A. We thank J. Peck and J. Strauss of the UNC Cryo-EM Core Facility for technical assistance in this project. W.Y. is partly supported by Program for Breakthrough Biomedical Research funded by the Sandler Foundation, University of California, San Francisco. L.Y.J. is a Howard Hughes Medical Institute investigator. We thank S.-L. Shyng for the plasmids encoding human Kir6.2 and SUR1. The Titan X Pascal used for this research was kindly donated to J.F.F. by the NVIDIA Corporation. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2021",

month = dec,

day = "2",

doi = "10.1038/s41586-021-04126-6",

language = "English",

volume = "600",

pages = "170--175",

journal = "Nature",

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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 2021, 'Structure, function and pharmacology of human itch GPCRs', Nature, vol. 600, no. 7887, pp. 170-175. https://doi.org/10.1038/s41586-021-04126-6

TY - JOUR

T1 - Structure, function and pharmacology of human itch GPCRs

AU - Cao, Can

AU - Kang, Hye Jin

AU - Singh, Isha

AU - Chen, He

AU - Zhang, Chengwei

AU - Ye, Wenlei

AU - Hayes, Byron W.

AU - Liu, Jing

AU - Gumpper, Ryan H.

AU - Bender, Brian J.

AU - Slocum, Samuel T.

AU - Krumm, Brian E.

AU - Lansu, Katherine

AU - McCorvy, John D.

AU - Kroeze, Wesley K.

AU - English, Justin G.

AU - DiBerto, Jeffrey F.

AU - Olsen, Reid H.J.

AU - Huang, Xi Ping

AU - Zhang, Shicheng

AU - Liu, Yongfeng

AU - Kim, Kuglae

AU - Karpiak, Joel

AU - Jan, Lily Y.

AU - Abraham, Soman N.

AU - Jin, Jian

AU - Shoichet, Brian K.

AU - Fay, Jonathan F.

AU - Roth, Bryan L.

N1 - Funding Information: Acknowledgements This work was supported by NIH grants U24DA116195 (to B.L.R., B.K.S. and J.J.) and R35GM122481 (to B.K.S.), and by the Michael Hooker Distinguished Professorship to B.L.R. and NIH grant R01-DK121969, R01-DK121032 and R56-AI139620 to S.N.A. We thank J. Peck and J. Strauss of the UNC Cryo-EM Core Facility for technical assistance in this project. W.Y. is partly supported by Program for Breakthrough Biomedical Research funded by the Sandler Foundation, University of California, San Francisco. L.Y.J. is a Howard Hughes Medical Institute investigator. We thank S.-L. Shyng for the plasmids encoding human Kir6.2 and SUR1. The Titan X Pascal used for this research was kindly donated to J.F.F. by the NVIDIA Corporation. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2021/12/2

Y1 - 2021/12/2

N2 - The MRGPRX family of receptors (MRGPRX1–4) is a family of mas-related G-protein-coupled receptors that have evolved relatively recently1. Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast cell-mediated hypersensitivity reactions2–5. MRGPRX2 couples to both Gi and Gq in mast cells6. Here we describe agonist-stabilized structures of MRGPRX2 coupled to Gi1 and Gq in ternary complexes with the endogenous peptide cortistatin-14 and with a synthetic agonist probe, respectively, and the development of potent antagonist probes for MRGPRX2. We also describe a specific MRGPRX4 agonist and the structure of this agonist in a complex with MRGPRX4 and Gq. Together, these findings should accelerate the structure-guided discovery of therapeutic agents for pain, itch and mast cell-mediated hypersensitivity.

AB - The MRGPRX family of receptors (MRGPRX1–4) is a family of mas-related G-protein-coupled receptors that have evolved relatively recently1. Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast cell-mediated hypersensitivity reactions2–5. MRGPRX2 couples to both Gi and Gq in mast cells6. Here we describe agonist-stabilized structures of MRGPRX2 coupled to Gi1 and Gq in ternary complexes with the endogenous peptide cortistatin-14 and with a synthetic agonist probe, respectively, and the development of potent antagonist probes for MRGPRX2. We also describe a specific MRGPRX4 agonist and the structure of this agonist in a complex with MRGPRX4 and Gq. Together, these findings should accelerate the structure-guided discovery of therapeutic agents for pain, itch and mast cell-mediated hypersensitivity.

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DO - 10.1038/s41586-021-04126-6

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VL - 600

SP - 170

EP - 175

JO - Nature

JF - Nature

IS - 7887

ER -

Structure, function and pharmacology of human itch GPCRs

Abstract

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