5MF4

Tubulin-Dictyostatin complex

5MF4 の概要

• エントリーDOI: 10.2210/pdb5mf4/pdb
• 関連するPDBエントリー: 5LXS 5LXT
• 分子名称: Tubulin alpha-1B chain, (3~{Z},5~{E},7~{R},8~{S},10~{S},11~{Z},13~{S},14~{R},15~{S},17~{S},20~{R},21~{S},22~{S})-22-[(2~{S},3~{Z})-hexa-3,5-dien-2-yl]-7,13,15,17,21-pentamethyl-8,10,14,20-tetrakis(oxidanyl)-1-oxacyclodocosa-3,5,11-trien-2-one, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (13 entities in total)
• 機能のキーワード: cell cycle, tubulin fold, cytoskeleton, microtubule
• 由来する生物種: Rattus norvegicus (Norway Rat); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 265926.91

構造登録者

Trigili, C.,Barasoain, I.,Sanchez-Murcia, P.A.,Bargsten, K.,Redondo-Horcajo, M.,Nogales, A.,Gardner, N.M.,Meyer, A.,Naylor, G.J.,Gomez-Rubio, E.,Gago, F.,Steinmetz, M.O.,Paterson, I.,Prota, A.E.,Diaz, J.F. (登録日: 2016-11-17, 公開日: 2017-09-20, 最終更新日: 2024-01-17)

主引用文献

Trigili, C.,Barasoain, I.,Sanchez-Murcia, P.A.,Bargsten, K.,Redondo-Horcajo, M.,Nogales, A.,Gardner, N.M.,Meyer, A.,Naylor, G.J.,Gomez-Rubio, E.,Gago, F.,Steinmetz, M.O.,Paterson, I.,Prota, A.E.,Diaz, J.F.
Structural Determinants of the Dictyostatin Chemotype for Tubulin Binding Affinity and Antitumor Activity Against Taxane- and Epothilone-Resistant Cancer Cells.
ACS Omega, 1:1192-1204, 2016

PubMed Abstract: A combined biochemical, structural, and cell biology characterization of dictyostatin is described, which enables an improved understanding of the structural determinants responsible for the high-affinity binding of this anticancer agent to the taxane site in microtubules (MTs). The study reveals that this macrolide is highly optimized for MT binding and that only a few of the structural modifications featured in a library of synthetic analogues resulted in small gains in binding affinity. The high efficiency of the dictyostatin chemotype in overcoming various kinds of clinically relevant resistance mechanisms highlights its potential for therapeutic development for the treatment of drug-resistant tumors. A structural explanation is advanced to account for the synergy observed between dictyostatin and taxanes on the basis of their differential effects on the MT lattice. The X-ray crystal structure of a tubulin-dictyostatin complex and additional molecular modeling have allowed the rationalization of the structure-activity relationships for a set of synthetic dictyostatin analogues, including the highly active hybrid with discodermolide. Altogether, the work reported here is anticipated to facilitate the improved design and synthesis of more efficacious dictyostatin analogues and hybrids with other MT-stabilizing agents.

PubMed: 30023505
DOI: 10.1021/acsomega.6b00317

実験手法

X-RAY DIFFRACTION (2.3 Å)