6Y4M

Structure of Tubulin Tyrosine Ligase in Complex with Tb111

6Y4M の概要

• エントリーDOI: 10.2210/pdb6y4m/pdb
• 分子名称: Tubulin alpha-1B chain, (2~{R})-1-methylpiperidine-2-carboxylic acid, [(1~{R},3~{R})-1-acetyloxy-1-[4-methanoyl-5-(2-phenylmethoxyethyl)-2,3-dihydro-1,3-thiazol-2-yl]-4-methyl-pentan-3-yl]-methyl-azanium, ... (16 entities in total)
• 機能のキーワード: ttl, tubulin, ligase, complex
• 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: 265376.99

構造登録者

Gavrilyuk, J.,Nocek, B.,Rigol, S.,Nicolaou, K.C.,Stoll, V. (登録日: 2020-02-21, 公開日: 2021-03-31, 最終更新日: 2024-06-19)

主引用文献

Nicolaou, K.C.,Pan, S.,Pulukuri, K.K.,Ye, Q.,Rigol, S.,Erande, R.D.,Vourloumis, D.,Nocek, B.P.,Munneke, S.,Lyssikatos, J.,Valdiosera, A.,Gu, C.,Lin, B.,Sarvaiaya, H.,Trinidad, J.,Sandoval, J.,Lee, C.,Hammond, M.,Aujay, M.,Taylor, N.,Pysz, M.,Purcell, J.W.,Gavrilyuk, J.
Design, Synthesis, and Biological Evaluation of Tubulysin Analogues, Linker-Drugs, and Antibody-Drug Conjugates, Insights into Structure-Activity Relationships, and Tubulysin-Tubulin Binding Derived from X-ray Crystallographic Analysis.
J.Org.Chem., 86:3377-3421, 2021

PubMed Abstract: Molecular design, synthesis, and biological evaluation of tubulysin analogues, linker-drugs, and antibody-drug conjugates are described. Among the new discoveries reported is the identification of new potent analogues within the tubulysin family that carry a C11 alkyl ether substituent, rather than the usual ester structural motif at that position, a fact that endows the former with higher plasma stability than that of the latter. Also described herein are X-ray crystallographic analysis studies of two tubulin-tubulysin complexes formed within the α/β interface between two tubulin heterodimers and two highly potent tubulysin analogues, one of which exhibited a different binding mode to the one previously reported for tubulysin M. The X-ray crystallographic analysis-derived new insights into the binding modes of these tubulysin analogues explain their potencies and provide inspiration for further design, synthesis, and biological investigations within this class of antitumor agents. A number of these analogues were conjugated as payloads with appropriate linkers at different sites allowing their attachment onto targeting antibodies for cancer therapies. A number of such antibody-drug conjugates were constructed and tested, both in vivo and in vitro, leading to the identification of at least one promising ADC (Herceptin-), warranting further investigations.

PubMed: 33544599
DOI: 10.1021/acs.joc.0c02755

実験手法

X-RAY DIFFRACTION (3.34 Å)