7vfs

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Human N-type voltage gated calcium channel CaV2.2-alpha2/delta1-beta1 complex, apo state

Structural highlights

7vfs is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 2.8Å
Ligands:BMA, CA, NAG, PT5, R16, Y01
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CACB1_HUMAN Regulatory subunit of L-type calcium channels (PubMed:1309651, PubMed:15615847, PubMed:8107964). Regulates the activity of L-type calcium channels that contain CACNA1A as pore-forming subunit (By similarity). Regulates the activity of L-type calcium channels that contain CACNA1C as pore-forming subunit and increases the presence of the channel complex at the cell membrane (PubMed:15615847). Required for functional expression L-type calcium channels that contain CACNA1D as pore-forming subunit (PubMed:1309651). Regulates the activity of L-type calcium channels that contain CACNA1B as pore-forming subunit (PubMed:8107964).[UniProtKB:P19517][1] [2] [3]

Publication Abstract from PubMed

N-type voltage-gated calcium (Ca(V)) channels mediate Ca(2+) influx at presynaptic terminals in response to action potentials and play vital roles in synaptogenesis, release of neurotransmitters, and nociceptive transmission. Here, we elucidate a cryo-electron microscopy (cryo-EM) structure of the human Ca(V)2.2 complex in apo, ziconotide-bound, and two Ca(V)2.2-specific pore blockers-bound states. The second voltage-sensing domain (VSD) is captured in a resting-state conformation, trapped by a phosphatidylinositol 4,5-bisphosphate (PIP(2)) molecule, which is distinct from the other three VSDs of Ca(V)2.2, as well as activated VSDs observed in previous structures of Ca(V) channels. This structure reveals the molecular basis for the unique inactivation process of Ca(V)2.2 channels, in which the intracellular gate formed by S6 helices is closed and a W-helix from the domain II-III linker stabilizes closed-state inactivation. The structures of this inactivated, drug-bound complex lay a solid foundation for developing new state-dependent blockers for treatment of chronic pain.

Closed-state inactivation and pore-blocker modulation mechanisms of human Ca(V)2.2.,Dong Y, Gao Y, Xu S, Wang Y, Yu Z, Li Y, Li B, Yuan T, Yang B, Zhang XC, Jiang D, Huang Z, Zhao Y Cell Rep. 2021 Nov 2;37(5):109931. doi: 10.1016/j.celrep.2021.109931. PMID:34731621[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
6 reviews cite this structure
Druggability of Voltage-Gated Sodium Channels-Exploring Old and New Drug Receptor Sites.
Wisedchaisri et al. (2022)
5 more
19 other articles
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See Also

References

  1. ↑ Williams ME, Feldman DH, McCue AF, Brenner R, Velicelebi G, Ellis SB, Harpold MM. Structure and functional expression of alpha 1, alpha 2, and beta subunits of a novel human neuronal calcium channel subtype. Neuron. 1992 Jan;8(1):71-84. PMID:1309651 doi:10.1016/0896-6273(92)90109-q
  2. ↑ Cohen RM, Foell JD, Balijepalli RC, Shah V, Hell JW, Kamp TJ. Unique modulation of L-type Ca2+ channels by short auxiliary beta1d subunit present in cardiac muscle. Am J Physiol Heart Circ Physiol. 2005 May;288(5):H2363-74. PMID:15615847 doi:10.1152/ajpheart.00348.2004
  3. ↑ Brust PF, Simerson S, McCue AF, Deal CR, Schoonmaker S, Williams ME, Veliçelebi G, Johnson EC, Harpold MM, Ellis SB. Human neuronal voltage-dependent calcium channels: studies on subunit structure and role in channel assembly. Neuropharmacology. 1993 Nov;32(11):1089-102. PMID:8107964 doi:10.1016/0028-3908(93)90004-m
  4. ↑ Dong Y, Gao Y, Xu S, Wang Y, Yu Z, Li Y, Li B, Yuan T, Yang B, Zhang XC, Jiang D, Huang Z, Zhao Y. Closed-state inactivation and pore-blocker modulation mechanisms of human Ca(V)2.2. Cell Rep. 2021 Nov 2;37(5):109931. PMID:34731621 doi:10.1016/j.celrep.2021.109931

Contents


PDB ID 7vfs

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OCA

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