膜ステロールによる滑らかな刺激がヘッジホッグ経路の活性化を促す

Ishan Deshpande¹, Jiahao Liang¹, Danielle Hedeen^2,3

¹Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.

Nature

|July 3, 2019

まとめ

ヘッジホッグの信号は発達と再生に不可欠ですコレステロールの構造を明らかにした.

科学分野:

生物化学
分子生物学
構造生物学

背景:

ヘッジホッグの信号は胚の発達と組織再生に不可欠です
制御不能のヘッジホッグ信号は基礎細胞癌や髄芽細胞腫のような癌に関与しています
スムージド (SMO) がヘッジホッグタンパク質によって活性化される正確なメカニズムは不明である.

研究の目的:

アクティブマウススムートネス (SMO) タンパク質の結晶構造を決定する.
アゴニストとコレステロールによるSMO活性化の構造的基礎を解明する.
パッチド-1 (PTCH1) によってSMOの調節を理解し,治療戦略を伝える.

主な方法:

SAG21kとナノボディに結合したマウスSMOのX線結晶学.
分子力学シミュレーション
信号経路の研究

主要な成果:

活性SMOの結晶構造を決定し,アゴニストSAG21kと安定化ナノボディとの相互作用を明らかにした.
SMOの活性化に不可欠なコレステロールは,以前のモデルとは異なり,7つのトランスメブランポケットに結合します.
PTCH1の無活性化により,ステロールがSMOにアクセスし,活性化を誘導するメカニズムが提案されています.

結論:

この研究は,SMOの活性化の構造的メカニズムを明らかにし,トランスメブランポケットにコレステロールの結合を伴う.
これは,ヘッジホッグのシグナリングにおける PTCH1-SMO 規制の構造的基盤を提供します.
発見は,がん治療におけるSMO阻害剤に対する耐性を克服するための戦略を開発するための洞察を提供します.

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