8fhs
From Proteopedia
(Difference between revisions)
| Line 16: | Line 16: | ||
Ca(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. | Ca(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. | ||
| - | + | , PMID:37972591<ref>PMID:37972591</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> | ||
Current revision
Human L-type voltage-gated calcium channel Cav1.2 in the presence of amiodarone and sofosbuvir at 3.3 Angstrom resolution
| |||||||||||
Categories: Homo sapiens | Large Structures | Gao S | Yan N | Yao X
