Recognition Mechanism of a Novel Gabapentinoid Drug, Mirogabalin, for Recombinant Human α 2 δ1, a Voltage-Gated Calcium Channel Subunit.

Autor: Kozai D; Cellular and Structural Physiology Institute (CeSPI), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan; Japan Biological Informatics Consortium, 2-4-32 Aomi, Koto-ku, Tokyo 135-0063, Japan; Advanced Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8501, Japan., Numoto N; Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8501, Japan., Nishikawa K; CeSPIA Inc., 2-1-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan; Joint Research Course for Advanced Biomolecular Characterization, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan., Kamegawa A; Advanced Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8501, Japan; CeSPIA Inc., 2-1-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan., Kawasaki S; Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan., Hiroaki Y; Cellular and Structural Physiology Institute (CeSPI), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan; Japan Biological Informatics Consortium, 2-4-32 Aomi, Koto-ku, Tokyo 135-0063, Japan., Irie K; Cellular and Structural Physiology Institute (CeSPI), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan; Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan., Oshima A; Cellular and Structural Physiology Institute (CeSPI), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan; Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan; Institute for Glyco-core Research (iGCORE), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan., Hanzawa H; Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan., Shimada K; Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan., Kitano Y; Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan., Fujiyoshi Y; Advanced Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8501, Japan; CeSPIA Inc., 2-1-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan. Electronic address: yoshi.cesp@tmd.ac.jp.
Jazyk: angličtina
Zdroj: Journal of molecular biology [J Mol Biol] 2023 May 15; Vol. 435 (10), pp. 168049. Date of Electronic Publication: 2023 Mar 17.
DOI: 10.1016/j.jmb.2023.168049
Abstrakt: Mirogabalin is a novel gabapentinoid drug with a hydrophobic bicyclo substituent on the γ-aminobutyric acid moiety that targets the voltage-gated calcium channel subunit α 2 δ1. Here, to reveal the mirogabalin recognition mechanisms of α 2 δ1, we present structures of recombinant human α 2 δ1 with and without mirogabalin analyzed by cryo-electron microscopy. These structures show the binding of mirogabalin to the previously reported gabapentinoid binding site, which is the extracellular dCache_1 domain containing a conserved amino acid binding motif. A slight conformational change occurs around the residues positioned close to the hydrophobic group of mirogabalin. Mutagenesis binding assays identified that residues in the hydrophobic interaction region, in addition to several amino acid binding motif residues around the amino and carboxyl groups of mirogabalin, are critical for mirogabalin binding. The A215L mutation introduced to decrease the hydrophobic pocket volume predictably suppressed mirogabalin binding and promoted the binding of another ligand, L-Leu, with a smaller hydrophobic substituent than mirogabalin. Alterations of residues in the hydrophobic interaction region of α 2 δ1 to those of the α 2 δ2, α 2 δ3, and α 2 δ4 isoforms, of which α 2 δ3 and α 2 δ4 are gabapentin-insensitive, suppressed the binding of mirogabalin. These results support the importance of hydrophobic interactions in α 2 δ1 ligand recognition.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mirogabalin is a product of Daiichi Sankyo Co., Ltd.; Shohei Kawasaki and Hiroyuki Hanzawa are employees of Daiichi Sankyo RD Novare Co., Ltd.; Kousei Shimada and Yutaka Kitano are employees of Daiichi Sankyo Co., Ltd.; Yoshinori Fujiyoshi is a director of CeSPIA Inc. [http://www.cespia.co.jp/]; The other authors declare no competing interests.
(Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: