8IF3

Structure of human alpha-2/delta-1 with mirogabalin

Summary for 8IF3

• Entry DOI: 10.2210/pdb8if3/pdb
• EMDB information: 35399
• Descriptor: Voltage-dependent calcium channel subunit alpha-2/delta-1, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: gabapentinoid, cache domain, cryo-em, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 127019.61

Authors

Kozai, D.,Numoto, N.,Fujiyoshi, Y. (deposition date: 2023-02-17, release date: 2023-04-05, Last modification date: 2023-04-12)

Primary citation

Kozai, D.,Numoto, N.,Nishikawa, K.,Kamegawa, A.,Kawasaki, S.,Hiroaki, Y.,Irie, K.,Oshima, A.,Hanzawa, H.,Shimada, K.,Kitano, Y.,Fujiyoshi, Y.
Recognition Mechanism of a Novel Gabapentinoid Drug, Mirogabalin, for Recombinant Human alpha 2 delta 1, a Voltage-Gated Calcium Channel Subunit.
J.Mol.Biol., 435:168049-168049, 2023

PubMed Abstract: 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.

PubMed: 36933823
DOI: 10.1016/j.jmb.2023.168049

Experimental method

ELECTRON MICROSCOPY (3.2 Å)