4TUY

Tubulin-Rhizoxin complex

4TUY の概要

• エントリーDOI: 10.2210/pdb4tuy/pdb
• 関連するPDBエントリー: 4I4T 4I50 4I55 4IHJ 4IIJ 4O2A 4O2B 4O4H 4O4I 4O4J 4O4L
• 分子名称: Tubulin alpha-1B chain, (1R,2R,3E,5R,7R,8S,10S,13E,16R)-8-hydroxy-10-[(2S,3R,4E,6E,8E)-3-methoxy-4,8-dimethyl-9-(2-methyl-1,3-oxazol-4-yl)nona-4,6,8-trien-2-yl]-2,7-dimethyl-6,11,19-trioxatricyclo[14.3.1.0~5,7~]icosa-3,13-diene-12,18-dione, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 entities in total)
• 機能のキーワード: cell cycle, cytoskeleton, tubulin fold, rhizoxin
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• 細胞内の位置: Cytoplasm, cytoskeleton: P81947; Cytoplasm, cytoskeleton (By similarity): Q6B856; Golgi apparatus: P63043
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 265075.96

構造登録者

Prota, A.E.,Bargsten, K.,Diaz, J.F.,Marsh, M.,Cuevas, C.,Liniger, M.,Neuhaus, C.,Andreu, J.M.,Altmann, K.H.,Steinmetz, M.O. (登録日: 2014-06-25, 公開日: 2014-08-27, 最終更新日: 2023-12-20)

主引用文献

Prota, A.E.,Bargsten, K.,Diaz, J.F.,Marsh, M.,Cuevas, C.,Liniger, M.,Neuhaus, C.,Andreu, J.M.,Altmann, K.H.,Steinmetz, M.O.
A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs.
Proc.Natl.Acad.Sci.USA, 111:13817-13821, 2014

PubMed Abstract: The recent success of antibody-drug conjugates (ADCs) in the treatment of cancer has led to a revived interest in microtubule-destabilizing agents. Here, we determined the high-resolution crystal structure of the complex between tubulin and maytansine, which is part of an ADC that is approved by the US Food and Drug Administration (FDA) for the treatment of advanced breast cancer. We found that the drug binds to a site on β-tubulin that is distinct from the vinca domain and that blocks the formation of longitudinal tubulin interactions in microtubules. We also solved crystal structures of tubulin in complex with both a variant of rhizoxin and the phase 1 drug PM060184. Consistent with biochemical and mutagenesis data, we found that the two compounds bound to the same site as maytansine and that the structures revealed a common pharmacophore for the three ligands. Our results delineate a distinct molecular mechanism of action for the inhibition of microtubule assembly by clinically relevant agents. They further provide a structural basis for the rational design of potent microtubule-destabilizing agents, thus opening opportunities for the development of next-generation ADCs for the treatment of cancer.

PubMed: 25114240
DOI: 10.1073/pnas.1408124111

実験手法

X-RAY DIFFRACTION (2.1 Å)