钙通道 α2δ 亚基与加巴喷丁结合的结构基础。
Structural basis for Caαδ:gabapentin binding.
机构信息
Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
Departments of Biochemistry and Biophysics, and Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA.
出版信息
Nat Struct Mol Biol. 2023 Jun;30(6):735-739. doi: 10.1038/s41594-023-00951-7. Epub 2023 Mar 27.
Abstract
Gabapentinoid drugs for pain and anxiety act on the Caαδ-1 and Caαδ-2 subunits of high-voltage-activated calcium channels (Ca1s and Ca2s). Here we present the cryo-EM structure of the gabapentin-bound brain and cardiac Ca1.2/Caβ/Caαδ-1 channel. The data reveal a binding pocket in the Caαδ-1 dCache1 domain that completely encapsulates gabapentin and define Caαδ isoform sequence variations that explain the gabapentin binding selectivity of Caαδ-1 and Caαδ-2.
摘要
加巴喷丁类药物可作用于高电压激活钙通道的 Caαδ-1 和 Caαδ-2 亚基（Ca1s 和 Ca2s），以缓解疼痛和焦虑。在此，我们展示了结合加巴喷丁的脑和心脏 Ca1.2/Caβ/Caαδ-1 通道的冷冻电镜结构。数据揭示了位于 Caαδ-1 dCache1 结构域的一个结合口袋，该口袋完全包裹了加巴喷丁，并定义了 Caαδ 同工型序列变化，这些变化解释了 Caαδ-1 和 Caαδ-2 对加巴喷丁的结合选择性。
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