超ヘリルマッチングによるモジュラーペプチド結合タンパク質のデノボ設計

Kejia Wu^1,2,3, Hua Bai^1,2,4, Ya-Ting Chang⁵

¹Department of Biochemistry, University of Washington, Seattle, WA, USA.

Nature

|April 5, 2023

まとめ

科学者は特定のペプチド配列を結合する新種のタンパク質を設計しましたこれらの重複タンパク質は高い安定性と親和性を提供し,プロテオミクスと合成生物学における潜在的な応用がある.

科学分野:

タンパク質工学
構造生物学
合成生物学

背景:

配列特異のペプチド結合タンパク質の設計は,プロテオミクスと合成生物学にとって極めて重要です.
課題は,定義された構造が欠けているペプチドと埋もれたペプチド骨格群との水素結合の形成の必要性です.

研究の目的:

繰り返し配列でペプチドに結合する繰り返しユニットから成る新しいタンパク質を設計する
特定の結合のためにタンパク質の繰り返し単位とペプチドの繰り返し単位の1対1対応を確立する.

主な方法:

ゲオメトリック・ハッシングを用いて,互換性のあるタンパク質の骨格とペプチドック装置を特定した.
タンパク質のサイドチェーンとペプチドの骨格の間の二酸化水素結合に焦点を当てた.
安定性およびペプチド結合のための残りのタンパク質配列の最適化.

主要な成果:

6つの異なるトリペプチド-リピート配列をポリプロリンII形状で結合する,成功裏に設計されたリピートタンパク質.
タンパク質は超安定性を示し,ナノモラーからピコモラーへの親和性を持つ標的ペプチドの4〜6個のタンデムリピートに結合した.
結晶構造は,タンパク質のサイドチェーンとペプチドの背骨の間の水素結合の梯子を含め,設計された繰り返しの相互作用を確認しました.
結合界面の再設計により,反復しないペプチド配列と原生タンパク質の乱れた領域の特異性を達成した.

結論:

配列特異のペプチド結合タンパク質を繰り返し設計するための堅固な戦略を開発した.
設計されたタンパク質は高い親和性,安定性,特異性を持ち,幅広い応用の可能性があります.
先進的な生物学的応用のためのタンパク質-ペプチド相互作用の実現性を実証した.

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