8hma
Cryo-EM structure of human high-voltage activated L-type calcium channel CaV1.2 in complex with tetrandrine (TET)
Structural highlights
DiseaseCAC1C_HUMAN Defects in CACNA1C are the cause of Timothy syndrome (TS) [MIM:601005. TS is a disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities and autism.[1] [2] Defects in CACNA1C are the cause of Brugada syndrome type 3 (BRGDA3) [MIM:611875. A heart disease characterized by the association of Brugada syndrome with shortened QT intervals. Brugada syndrome is a tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs (called ventricular fibrillation), the individual will faint and may die in a few minutes if the heart is not reset.[3] FunctionCAC1C_HUMAN Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1C gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin-GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1C subunit play an important role in excitation-contraction coupling in the heart. The various isoforms display marked differences in the sensitivity to DHP compounds. Binding of calmodulin or CABP1 at the same regulatory sites results in an opposit effects on the channel function.[4] [5] [6] [7] [8] [9] Publication Abstract from PubMedThe voltage-gated calcium channel Ca(V)1.2 is essential for cardiac and vessel smooth muscle contractility and brain function. Accumulating evidence demonstrates that malfunctions of Ca(V)1.2 are involved in brain and heart diseases. Pharmacological inhibition of Ca(V)1.2 is therefore of therapeutic value. Here, we report cryo-EM structures of Ca(V)1.2 in the absence or presence of the antirheumatic drug tetrandrine or antihypertensive drug benidipine. Tetrandrine acts as a pore blocker in a pocket composed of S6(II), S6(III), and S6(IV) helices and forms extensive hydrophobic interactions with Ca(V)1.2. Our structure elucidates that benidipine is located in the D(III)-D(IV) fenestration site. Its hydrophobic sidechain, phenylpiperidine, is positioned at the exterior of the pore domain and cradled within a hydrophobic pocket formed by S5(DIII), S6(DIII), and S6(DIV) helices, providing additional interactions to exert inhibitory effects on both L-type and T-type voltage gated calcium channels. These findings provide the structural foundation for the rational design and optimization of therapeutic inhibitors of voltage-gated calcium channels. , PMID:38555290[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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