Structural insight into the activation mechanism of MrgD with heterotrimeric Gi-protein revealed by cryo-EM.

Autor: Suzuki S; Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.; Advanced Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan., Iida M; Division of Biological Science, School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan., Hiroaki Y; Cellular and Structural Physiology Institute (CeSPI), Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.; Japan Biological Informatics Consortium (JBIC), Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan., Tanaka K; Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.; Cellular and Structural Physiology Institute (CeSPI), Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan., Kawamoto A; Institute for Protein Research, Osaka University, Suita, Osaka, 565-0871, Japan.; Japan Science and Technology Agency, PRESTO, Saitama, 332-0012, Japan., Kato T; Institute for Protein Research, Osaka University, Suita, Osaka, 565-0871, Japan., Oshima A; Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan. atsu@cespi.nagoya-u.ac.jp.; Cellular and Structural Physiology Institute (CeSPI), Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan. atsu@cespi.nagoya-u.ac.jp.; Institute for Glyco-core Research (iGCORE), Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan. atsu@cespi.nagoya-u.ac.jp.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2022 Jul 15; Vol. 5 (1), pp. 707. Date of Electronic Publication: 2022 Jul 15.
DOI: 10.1038/s42003-022-03668-3
Abstrakt: MrgD, a member of the Mas-related G protein-coupled receptor (MRGPR) family, has high basal activity for Gi activation. It recognizes endogenous ligands, such as β-alanine, and is involved in pain and itch signaling. The lack of a high-resolution structure for MrgD hinders our understanding of whether its activation is ligand-dependent or constitutive. Here, we report two cryo-EM structures of the MrgD-Gi complex in the β-alanine-bound and apo states at 3.1 Å and 2.8 Å resolution, respectively. These structures show that β-alanine is bound to a shallow pocket at the extracellular domains. The extracellular half of the sixth transmembrane helix undergoes a significant movement and is tightly packed into the third transmembrane helix through hydrophobic residues, creating the active form. Our structures demonstrate a structural basis for the characteristic ligand recognition of MrgD. These findings provide a framework to guide drug designs targeting the MrgD receptor.
(© 2022. The Author(s).)
Databáze: MEDLINE
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