イソフォーム選択小分子抗体によるNav1. 7抑制の構造的基礎
Shivani Ahuja1, Susmith Mukund1, Lunbin Deng2
1Department of Structural Biology, Genentech Inc., South San Francisco, CA 94080, USA.
Science (New York, N.Y.)
|December 19, 2015
まとめ
研究者たちは,電圧ゲート型ナトリウムチャネルNav1.7の構造を決定する新しいタンパク質戦略を開発しました. 選択性阻害剤の新たな結合部位を明らかにし 痛みに対する薬の開発を助長しました
科学分野:
- 分子生物学
- 構造生物学
- 神経科学
- 薬理学について
背景:
- ボルテージゲートされたナトリウム (Nav) チャンネルは,興奮性の細胞におけるアクションポテンシャル伝播に不可欠である.
- NAVチャネルは,心血管疾患と神経疾患の主要な治療標的であるが,アイソフォーム選択的阻害剤は,高シーケンスホモロジーのために設計することが困難である.
- 人間のNav1.7チャネルは痛みの知覚に関与しており,重要な薬物標的となっています.
研究 の 目的:
- NAVチャネルの構造研究における課題を克服するためのタンパク質エンジニアリング戦略を開発する.
- ヒトのNav1. 7チャネルに結合する新しい受容体の高解像度構造を決定する.
- Nav1.7 の電圧感知と阻害の分子基礎を明らかにする.
主な方法:
- Nav1.7チャネルの結晶化を促進するためにタンパク質エンジニアリング戦略を採用しました.
- 新しい抗体 (例えば,GX-936) との複合体におけるNav1.7チャネルの結晶構造を決定した.
- アイソフォーム選択性の結合相互作用と構造的決定因子を分析した.
主要な成果:
- Nav1.7チャネルの電圧センサードメインIV (VSD4) の内にある新しい受容体サイトを特定した.
- アンタゴニストが活性化されたVSD4に結合し,電圧センサトラッピングメカニズムを通じてその無活性化に抵抗することを実証した.
- S2 と S3 ヘリクスの特定の残留物は,膜フォスホリピドとともに,Nav1. 7の抑制と選択性にとって重要であることが明らかになった.
結論:
- この研究は,Nav1. 7チャンネルにおける新しい阻害部位に関する最初の構造的洞察を提供します.
- ボルテージセンサトラッピングメカニズムは,Navチャネル阻害のための新しいパラダイムを提供します.
- これらの発見は,疼痛管理のための強力で同型選択的なNav1. 7抗剤の設計のための構造的設計図を確立します.
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