7O07

14-3-3sigma covalently bound to peptide (chloroacetamide-Cys interaction)

7O07 の概要

• エントリーDOI: 10.2210/pdb7o07/pdb
• 分子名称: 14-3-3 protein sigma, Transcriptional coactivator YAP1, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: 14-3-3, covalent peptide binding, protein/peptide interaction, peptide binding protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 27964.92

構造登録者

Somsen, B.A.,Ottmann, C. (登録日: 2021-03-25, 公開日: 2021-10-13, 最終更新日: 2024-02-07)

主引用文献

Tivon, B.,Gabizon, R.,Somsen, B.A.,Cossar, P.J.,Ottmann, C.,London, N.
Covalent flexible peptide docking in Rosetta.
Chem Sci, 12:10836-10847, 2021

PubMed Abstract: Electrophilic peptides that form an irreversible covalent bond with their target have great potential for binding targets that have been previously considered undruggable. However, the discovery of such peptides remains a challenge. Here, we present Rosetta CovPepDock, a computational pipeline for peptide docking that incorporates covalent binding between the peptide and a receptor cysteine. We applied CovPepDock retrospectively to a dataset of 115 disulfide-bound peptides and a dataset of 54 electrophilic peptides. It produced a top-five scoring, near-native model, in 89% and 100% of the cases when docking from the native conformation, and 20% and 90% when docking from an extended peptide conformation, respectively. In addition, we developed a protocol for designing electrophilic peptide binders based on known non-covalent binders or protein-protein interfaces. We identified 7154 peptide candidates in the PDB for application of this protocol. As a proof-of-concept we validated the protocol on the non-covalent complex of 14-3-3σ and YAP1 phosphopeptide. The protocol identified seven highly potent and selective irreversible peptide binders. The predicted binding mode of one of the peptides was validated using X-ray crystallography. This case-study demonstrates the utility and impact of CovPepDock. It suggests that many new electrophilic peptide binders can be rapidly discovered, with significant potential as therapeutic molecules and chemical probes.

PubMed: 34476063
DOI: 10.1039/d1sc02322e

実験手法

X-RAY DIFFRACTION (1.2 Å)