8if3: Difference between revisions
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==Structure of human alpha-2/delta-1 with mirogabalin== | ==Structure of human alpha-2/delta-1 with mirogabalin== | ||
<StructureSection load='8if3' size='340' side='right'caption='[[8if3]], [[Resolution|resolution]] 3. | <StructureSection load='8if3' size='340' side='right'caption='[[8if3]], [[Resolution|resolution]] 3.23Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8if3]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8IF3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8IF3 FirstGlance]. <br> | <table><tr><td colspan='2'>[[8if3]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8IF3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8IF3 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8X9:2-[( | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.23Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8X9:2-[(1~{R},5~{S},6~{S})-6-(aminomethyl)-3-ethyl-6-bicyclo[3.2.0]hept-3-enyl]ethanoic+acid'>8X9</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8if3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8if3 OCA], [https://pdbe.org/8if3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8if3 RCSB], [https://www.ebi.ac.uk/pdbsum/8if3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8if3 ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8if3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8if3 OCA], [https://pdbe.org/8if3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8if3 RCSB], [https://www.ebi.ac.uk/pdbsum/8if3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8if3 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
[https://www.uniprot.org/uniprot/CA2D1_HUMAN CA2D1_HUMAN] Familial short QT syndrome;Brugada syndrome. | [https://www.uniprot.org/uniprot/CA2D1_HUMAN 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 == | == Function == | ||
[https://www.uniprot.org/uniprot/CA2D1_HUMAN CA2D1_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). | [https://www.uniprot.org/uniprot/CA2D1_HUMAN 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).<ref>PMID:35293990</ref> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == 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. | 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 | 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<ref>PMID:36933823</ref> | ||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 8if3" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 8if3" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Ion channels 3D structures|Ion channels 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
Latest revision as of 10:22, 21 November 2024
Structure of human alpha-2/delta-1 with mirogabalinStructure of human alpha-2/delta-1 with mirogabalin
Structural highlights
DiseaseCA2D1_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. FunctionCA2D1_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).[1] 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 May 15;435(10):168049. doi: 10.1016/j.jmb.2023.168049. Epub 2023 , Mar 17. PMID:36933823[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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