リガンド発見のための多循環ペプチドライブラリの開発のためのシステインフレームワークのデノボ発見
Jinjing Li1, Hongtan Liu1, Shuling Xiao1
1The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P. R. China.
Journal of the American Chemical Society
|December 13, 2023
まとめ
研究者らは新型のシステインフレームワークを ディスルファイドに富んだペプチド (DRP) の発見に用いた新しい方法を開発した. このアプローチにより,強力なペプチドリガンドと薬物を発見するための多様なDRPライブラリを作成できます.
科学分野:
- 生物化学
- 構造生物学
- ペプチドの設計
背景:
- 保存されたシステインの枠組みは,二硫化物豊富なペプチド (DRP) の構造的多様性にとって極めて重要です.
- 頑丈な折り畳み性を持つ新しいシステインのフレームワークを発見するための既存の方法は限られています.
- フレームワークの発見のための新しい戦略が必要です.
研究 の 目的:
- 硫化物豊富なペプチドのための新しいシステインフレームワークの発見のための一般的な方法を開発する.
- 堅固な折り畳み性とファグ表示システムとの互換性を有するシステインのフレームワークを特定する.
- 高結合率のペプチドリガンドの迅速な発見を可能にします.
主な方法:
- ファグ表面上の2つのDRP間の酸化折り畳みを利用した"タッチストーン"ベースの戦略が考案されました.
- ランダムな配列をスクリーニングし,ユニークなシステインフレームワークを特定しました.
- 特定されたフレームワークは,多サイクル DRP ライブラリを開発するために使用されました.
主要な成果:
- ファグ表示と幅広いシーケンス耐性を有する新しいシステインフレームワークが発見されました.
- 新しいフレームワークは,多サイクル DRP ライブラリの開発を容易にした.
- 低ナノモラーおよびピコモラー結合親和性を持つペプチドリガンドは急速に発見されました.
結論:
- "タッチストーン"ベースの戦略は,DRPのシーケンスと構造空間を探索するための前例のない方法を提供します.
- このアプローチは,多循環ペプチド結合体と薬物の設計と発見を大幅に前進させる.
- この研究は,二硫化物豊富なペプチドの研究分野に革命をもたらす可能性を秘めています.
関連する概念動画
00:49Ligand Binding and Linkage
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence the...
02:04Protein-protein Interfaces
Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a polypeptide...
02:40Ligand Binding Sites
Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
02:40Ligand Binding Sites
Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...