6GHP

14-3-3sigma in complex with a TASK3 peptide stabilized by semi-synthetic natural product FC-NAc

6GHP の概要

• エントリーDOI: 10.2210/pdb6ghp/pdb
• 分子名称: 14-3-3 protein sigma, Potassium channel subfamily K member 9, ~{N}-[(2~{S})-2-[(1~{E},3~{R},4~{S},8~{R},9~{R},10~{R},11~{S},14~{S})-14-(methoxymethyl)-3,10-dimethyl-8-[(2~{S},3~{R},4~{S},5~{S},6~{R})-6-(2-methylbut-3-en-2-yloxymethyl)-3,4,5-tris(oxidanyl)oxan-2-yl]oxy-4,9-bis(oxidanyl)-6-tricyclo[9.3.0.0^{3,7}]tetradeca-1,6-dienyl]propyl]ethanamide, ... (6 entities in total)
• 機能のキーワード: potassium channel, natural product, ppi, stabilizer, signaling 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: 28123.85

構造登録者

Andrei, S.A.,de Vink, P.J.,Brunsveld, L.,Ottmann, C.,Higuchi, Y. (登録日: 2018-05-08, 公開日: 2018-08-01, 最終更新日: 2018-10-17)

主引用文献

Andrei, S.A.,de Vink, P.,Sijbesma, E.,Han, L.,Brunsveld, L.,Kato, N.,Ottmann, C.,Higuchi, Y.
Rationally Designed Semisynthetic Natural Product Analogues for Stabilization of 14-3-3 Protein-Protein Interactions.
Angew. Chem. Int. Ed. Engl., 57:13470-13474, 2018

PubMed Abstract: The natural product family of fusicoccanes are stabilizers of 14-3-3 mediated protein-protein interactions (PPIs), some of which possess antitumor activity. In this study, the first use of molecular dynamics (MD) to rationally design PPI stabilizers with increased potency is presented. Synthesis of a focused library, with subsequent characterization by fluorescence polarization, mutational studies, and X-ray crystallography confirmed the power of the MD-based design approach, revealing the potential for an additional hydrogen bond with the 14-3-3 protein to lead to significantly increased potency. Additionally, these compounds exert their action in a cellular environment with increased potency. The newly found polar interaction could provide an anchoring point for new small-molecule PPI stabilizers. These results facilitate the development of fusicoccanes towards drugs or tool compounds, as well as allowing the study of the fundamental principles behind PPI stabilization.

PubMed: 30025189
DOI: 10.1002/anie.201806584

実験手法

X-RAY DIFFRACTION (1.95 Å)