6GHP
14-3-3sigma in complex with a TASK3 peptide stabilized by semi-synthetic natural product FC-NAc
Summary for 6GHP
| Entry DOI | 10.2210/pdb6ghp/pdb |
| Descriptor | 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) |
| Functional Keywords | potassium channel, natural product, ppi, stabilizer, signaling protein |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 28161.14 |
| Authors | Andrei, S.A.,de Vink, P.J.,Brunsveld, L.,Ottmann, C.,Higuchi, Y. (deposition date: 2018-05-08, release date: 2018-08-01, Last modification date: 2024-11-13) |
| Primary citation | 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 Cited by 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: 30025189DOI: 10.1002/anie.201806584 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
Download full validation report
