EMD-37473
Human L-type voltage-gated calcium channel Cav1.2 in the presence of calciseptine at 3.2 Angstrom resolution
EMD-37473
Single-particle3.2 Å

Map released: 06/12/2023
Last modified: 13/11/2024
Sample Organism:
Homo sapiens,
Dendroaspis polylepis polylepis
Sample: Cav1.2
Fitted models: 8we7 (Avg. Q-score: 0.436)
Deposition Authors: Gao S, Yao X, Yan N
Sample: Cav1.2
Fitted models: 8we7 (Avg. Q-score: 0.436)
Deposition Authors: Gao S, Yao X, Yan N
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
(2023) Cell , 186 , 5363 - 5374.e16



(2023) Cell , 186 , 5363 - 5374.e16
Abstract:
Cav1.2 channels play crucial roles in various neuronal and physiological processes. Here, we present cryo-EM structures of human Cav1.2, 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 VSDII. 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 Nav channels, a series of structural changes occur, including upward movement of VSDII coupled with dilation of the selectivity filter and its surrounding segments in repeat III. Meanwhile, S4-5III merges with S5III to become a single helix, resulting in a widened but still non-conductive intracellular gate.
Cav1.2 channels play crucial roles in various neuronal and physiological processes. Here, we present cryo-EM structures of human Cav1.2, 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 VSDII. 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 Nav channels, a series of structural changes occur, including upward movement of VSDII coupled with dilation of the selectivity filter and its surrounding segments in repeat III. Meanwhile, S4-5III merges with S5III to become a single helix, resulting in a widened but still non-conductive intracellular gate.