9ayk: Difference between revisions
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==Cryo-EM structure of human Cav3.2 with ML218== | |||
<StructureSection load='9ayk' size='340' side='right'caption='[[9ayk]], [[Resolution|resolution]] 3.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[9ayk]] 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=9AYK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9AYK FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1AHJ:3,5-dichloro-N-{[(1R,5S,6r)-3-(3,3-dimethylbutyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl}benzamide'>A1AHJ</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=JL3:[(2~{R})-3-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-2-pentadecanoyloxy-propyl]+pentadecanoate'>JL3</scene>, <scene name='pdbligand=LPE:1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE'>LPE</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</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=9ayk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9ayk OCA], [https://pdbe.org/9ayk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9ayk RCSB], [https://www.ebi.ac.uk/pdbsum/9ayk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9ayk ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The Ca(v)3.2 subtype of T-type calcium channels has been targeted for developing analgesics and anti-epileptics for its role in pain and epilepsy. Here we present the cryo-EM structures of Ca(v)3.2 alone and in complex with four T-type calcium channel selective antagonists with overall resolutions ranging from 2.8 A to 3.2 A. The four compounds display two binding poses. ACT-709478 and TTA-A2 both place their cyclopropylphenyl-containing ends in the central cavity to directly obstruct ion flow, meanwhile extending their polar tails into the IV-I fenestration. TTA-P2 and ML218 project their 3,5-dichlorobenzamide groups into the II-III fenestration and place their hydrophobic tails in the cavity to impede ion permeation. The fenestration-penetrating mode immediately affords an explanation for the state-dependent activities of these antagonists. Structure-guided mutational analysis identifies several key residues that determine the T-type preference of these drugs. The structures also suggest the role of an endogenous lipid in stabilizing drug binding in the central cavity. | |||
Structural basis for human Ca(v)3.2 inhibition by selective antagonists.,Huang J, Fan X, Jin X, Lyu C, Guo Q, Liu T, Chen J, Davakan A, Lory P, Yan N Cell Res. 2024 Jun;34(6):440-450. doi: 10.1038/s41422-024-00959-8. Epub 2024 Apr , 11. PMID:38605177<ref>PMID:38605177</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 9ayk" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Fan X]] | |||
[[Category: Huang J]] | |||
[[Category: Yan N]] | |||
Latest revision as of 05:29, 12 June 2024
Cryo-EM structure of human Cav3.2 with ML218
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