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TitleRecognition Mechanism of a Novel Gabapentinoid Drug, Mirogabalin, for Recombinant Human αδ1, a Voltage-Gated Calcium Channel Subunit.
Journal, issue, pagesJ Mol Biol, Vol. 435, Issue 10, Page 168049, Year 2023
Publish dateMar 17, 2023
AuthorsDaisuke Kozai / Nobutaka Numoto / Kouki Nishikawa / Akiko Kamegawa / Shohei Kawasaki / Yoko Hiroaki / Katsumasa Irie / Atsunori Oshima / Hiroyuki Hanzawa / Kousei Shimada / Yutaka Kitano / Yoshinori Fujiyoshi /
PubMed AbstractMirogabalin 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.
External linksJ Mol Biol / PubMed:36933823
MethodsEM (single particle)
Resolution3.23 Å
Structure data

35399

8if3

EMDB-35399, PDB-8if3:
Structure of human alpha-2/delta-1 with mirogabalin
Method: EM (single particle) / Resolution: 3.23 Å

35400

8if4

EMDB-35400, PDB-8if4:
Structure of human alpha-2/delta-1 without mirogabalin
Method: EM (single particle) / Resolution: 3.23 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-8X9:
2-[(1R,5S,6S)-6-(aminomethyl)-3-ethyl-6-bicyclo[3.2.0]hept-3-enyl]acetic acid

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / gabapentinoid / Cache domain / cryo-EM

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