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-Structure paper
タイトル | Structures of the R-type human Ca2.3 channel reveal conformational crosstalk of the intracellular segments. |
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ジャーナル・号・ページ | Nat Commun, Vol. 13, Issue 1, Page 7358, Year 2022 |
掲載日 | 2022年11月30日 |
著者 | Xia Yao / Yan Wang / Zhifei Wang / Xiao Fan / Di Wu / Jian Huang / Alexander Mueller / Sarah Gao / Miaohui Hu / Carol V Robinson / Yong Yu / Shuai Gao / Nieng Yan / |
PubMed 要旨 | The R-type voltage-gated Ca (Ca) channels Ca2.3, widely expressed in neuronal and neuroendocrine cells, represent potential drug targets for pain, seizures, epilepsy, and Parkinson's disease. Despite ...The R-type voltage-gated Ca (Ca) channels Ca2.3, widely expressed in neuronal and neuroendocrine cells, represent potential drug targets for pain, seizures, epilepsy, and Parkinson's disease. Despite their physiological importance, there have lacked selective small-molecule inhibitors targeting these channels. High-resolution structures may aid rational drug design. Here, we report the cryo-EM structure of human Ca2.3 in complex with α2δ-1 and β3 subunits at an overall resolution of 3.1 Å. The structure is nearly identical to that of Ca2.2, with VSD in the down state and the other three VSDs up. A phosphatidylinositol 4,5-bisphosphate (PIP2) molecule binds to the interface of VSD and the tightly closed pore domain. We also determined the cryo-EM structure of a Ca2.3 mutant in which a Ca2-unique cytosolic helix in repeat II (designated the CH2 helix) is deleted. This mutant, named ΔCH2, still reserves a down VSD, but PIP2 is invisible and the juxtamembrane region on the cytosolic side is barely discernible. Our structural and electrophysiological characterizations of the wild type and ΔCH2 Ca2.3 show that the CH2 helix stabilizes the inactivated conformation of the channel by tightening the cytosolic juxtamembrane segments, while CH2 helix is not necessary for locking the down state of VSD. |
リンク | Nat Commun / PubMed:36446785 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.1 Å |
構造データ | EMDB-28529, PDB-8epl: EMDB-28530, PDB-8epm: |
化合物 | ChemComp-CA: ChemComp-CLR: ChemComp-3PE: ChemComp-PT5: ChemComp-NAG: |
由来 |
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キーワード | TRANSPORT PROTEIN / Cav2.3 / Channels / Calcium Ion-Selective |