8we9
Human L-type voltage-gated calcium channel Cav1.2 (Class I) in the presence of pinaverium at 3.0 Angstrom resolution
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 PubMedCa(v)1.2 channels play crucial roles in various neuronal and physiological processes. Here, we present cryo-EM structures of human Ca(v)1.2, both in its apo form and in complex with several drugs, as well as the peptide neurotoxin calciseptine. Most structures, apo or bound to calciseptine, amlodipine, or a combination of amiodarone and sofosbuvir, exhibit a consistent inactivated conformation with a sealed gate, three up voltage-sensing domains (VSDs), and a down VSD(II). Calciseptine sits on the shoulder of the pore domain, away from the permeation path. In contrast, when pinaverium bromide, an antispasmodic drug, is inserted into a cavity reminiscent of the IFM-binding site in Na(v) channels, a series of structural changes occur, including upward movement of VSD(II) coupled with dilation of the selectivity filter and its surrounding segments in repeat III. Meanwhile, S4-5(III) merges with S5(III) to become a single helix, resulting in a widened but still non-conductive intracellular gate. Structural basis for human Ca(v)1.2 inhibition by multiple drugs and the neurotoxin calciseptine.,Gao S, Yao X, Chen J, Huang G, Fan X, Xue L, Li Z, Wu T, Zheng Y, Huang J, Jin X, Wang Y, Wang Z, Yu Y, Liu L, Pan X, Song C, Yan N Cell. 2023 Nov 22;186(24):5363-5374.e16. doi: 10.1016/j.cell.2023.10.007. Epub , 2023 Nov 15. PMID:37972591[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
