regulation of membrane repolarization during action potential / positive regulation of high voltage-gated calcium channel activity / calcium ion transmembrane transport via high voltage-gated calcium channel / membrane depolarization during bundle of His cell action potential / L-type voltage-gated calcium channel complex / cardiac muscle cell action potential involved in contraction / regulation of ventricular cardiac muscle cell membrane repolarization / calcium ion transport into cytosol / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / voltage-gated calcium channel complex ...regulation of membrane repolarization during action potential / positive regulation of high voltage-gated calcium channel activity / calcium ion transmembrane transport via high voltage-gated calcium channel / membrane depolarization during bundle of His cell action potential / L-type voltage-gated calcium channel complex / cardiac muscle cell action potential involved in contraction / regulation of ventricular cardiac muscle cell membrane repolarization / calcium ion transport into cytosol / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / voltage-gated calcium channel complex / neuronal dense core vesicle / regulation of heart rate by cardiac conduction / calcium ion import across plasma membrane / regulation of calcium ion transport / voltage-gated calcium channel activity / sarcoplasmic reticulum / cellular response to amyloid-beta / calcium ion transport / extracellular exosome / metal ion binding / plasma membrane 類似検索 - 分子機能
VWA N-terminal / Voltage-dependent calcium channel, alpha-2/delta subunit, conserved region / VWA N-terminal / Neuronal voltage-dependent calcium channel alpha 2acd / von Willebrand factor type A domain / von Willebrand factor (vWF) type A domain / VWFA domain profile. / von Willebrand factor, type A / von Willebrand factor A-like domain superfamily 類似検索 - ドメイン・相同性
Japan Agency for Medical Research and Development (AMED)
日本
引用
ジャーナル: J Mol Biol / 年: 2023 タイトル: Recognition Mechanism of a Novel Gabapentinoid Drug, Mirogabalin, for Recombinant Human αδ1, a Voltage-Gated Calcium Channel Subunit. 著者: Daisuke Kozai / Nobutaka Numoto / Kouki Nishikawa / Akiko Kamegawa / Shohei Kawasaki / Yoko Hiroaki / Katsumasa Irie / Atsunori Oshima / Hiroyuki Hanzawa / Kousei Shimada / Yutaka Kitano / Yoshinori Fujiyoshi / 要旨: 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 αδ1. Here, to reveal the ...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 αδ1. Here, to reveal the mirogabalin recognition mechanisms of αδ1, we present structures of recombinant human αδ1 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 αδ1 to those of the αδ2, αδ3, and αδ4 isoforms, of which αδ3 and αδ4 are gabapentin-insensitive, suppressed the binding of mirogabalin. These results support the importance of hydrophobic interactions in αδ1 ligand recognition.