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Structure, function and pharmacology of human itch GPCRs.
Cao, Can; Kang, Hye Jin; Singh, Isha; Chen, He; Zhang, Chengwei; Ye, Wenlei; Hayes, Byron W; Liu, Jing; Gumpper, Ryan H; Bender, Brian J; Slocum, Samuel T; Krumm, Brian E; Lansu, Katherine; McCorvy, John D; Kroeze, Wesley K; English, Justin G; DiBerto, Jeffrey F; Olsen, Reid H J; Huang, Xi-Ping; Zhang, Shicheng; Liu, Yongfeng; Kim, Kuglae; Karpiak, Joel; Jan, Lily Y; Abraham, Soman N; Jin, Jian; Shoichet, Brian K; Fay, Jonathan F; Roth, Bryan L.
Afiliación
  • Cao C; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Kang HJ; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Singh I; Department of Pharmaceutical Sciences, University of California San Francisco, School of Medicine, San Francisco, CA, USA.
  • Chen H; Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Zhang C; Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Ye W; Department of Physiology, University of California, San Francisco, San Francisco, CA, USA.
  • Hayes BW; Department of Pathology, Duke University Medical Center, Durham, NC, USA.
  • Liu J; Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Gumpper RH; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Bender BJ; Department of Pharmaceutical Sciences, University of California San Francisco, School of Medicine, San Francisco, CA, USA.
  • Slocum ST; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Krumm BE; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Lansu K; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • McCorvy JD; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Kroeze WK; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
  • English JG; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • DiBerto JF; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Olsen RHJ; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • Huang XP; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Zhang S; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Liu Y; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Kim K; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Karpiak J; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Jan LY; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Abraham SN; Department of Pharmaceutical Sciences, University of California San Francisco, School of Medicine, San Francisco, CA, USA.
  • Jin J; Department of Physiology, University of California, San Francisco, San Francisco, CA, USA.
  • Shoichet BK; Howard Hughes Medical Institute, San Francisco, CA, USA.
  • Fay JF; Department of Pathology, Duke University Medical Center, Durham, NC, USA.
  • Roth BL; Program in Emerging Infectious Diseases, Duke-National University of Singapore, Singapore, Singapore.
Nature ; 600(7887): 170-175, 2021 12.
Article en En | MEDLINE | ID: mdl-34789874
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Prurito / Receptores de Neuropéptido / Microscopía por Crioelectrón / Receptores Acoplados a Proteínas G / Proteínas del Tejido Nervioso Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Nature Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Prurito / Receptores de Neuropéptido / Microscopía por Crioelectrón / Receptores Acoplados a Proteínas G / Proteínas del Tejido Nervioso Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Nature Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos