8if3

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

spinqualitylabelsall models 8if3, resolution 3.23Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8if3 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.23Å Ligands: 8X9, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease CA2D1_HUMAN Familial short QT syndrome;Non-specific early-onset epileptic encephalopathy;Brugada syndrome. The disease is caused by variants affecting the gene represented in this entry. Function CA2D1_HUMAN The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel (PubMed:35293990). Plays an important role in excitation-contraction coupling (By similarity). Publication Abstract from PubMed Mirogabalin 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 May 15;435(10):168049. doi: 10.1016/j.jmb.2023.168049. Epub 2023 , Mar 17. PMID:36933823 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ion channels 3D structures

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