8if4 | pdb_00008if4
Structure of human alpha-2/delta-1 without mirogabalin
Structural highlights
DiseaseCA2D1_HUMAN Familial short QT syndrome;Brugada syndrome. FunctionCA2D1_HUMAN The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Plays an important role in excitation-contraction coupling (By similarity). Publication Abstract from PubMedMirogabalin is a novel gabapentinoid drug with a hydrophobic bicyclo substituent on the gamma-aminobutyric acid moiety that targets the voltage-gated calcium channel subunit alpha(2)delta1. Here, to reveal the mirogabalin recognition mechanisms of alpha(2)delta1, we present structures of recombinant human alpha(2)delta1 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 alpha(2)delta1 to those of the alpha(2)delta2, alpha(2)delta3, and alpha(2)delta4 isoforms, of which alpha(2)delta3 and alpha(2)delta4 are gabapentin-insensitive, suppressed the binding of mirogabalin. These results support the importance of hydrophobic interactions in alpha(2)delta1 ligand recognition. Recognition Mechanism of a Novel Gabapentinoid Drug, Mirogabalin, for Recombinant Human alpha(2)delta1, a Voltage-Gated Calcium Channel Subunit.,Kozai D, Numoto N, Nishikawa K, Kamegawa A, Kawasaki S, Hiroaki Y, Irie K, Oshima A, Hanzawa H, Shimada K, Kitano Y, Fujiyoshi Y J Mol Biol. 2023 Mar 17;435(10):168049. doi: 10.1016/j.jmb.2023.168049. PMID:36933823[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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