5LP6

Crystal structure of Tubulin-Stathmin-TTL-Thiocolchicine Complex

5LP6 の概要

• エントリーDOI: 10.2210/pdb5lp6/pdb
• 分子名称: Tubulin alpha-1B chain, ~{N}-[(7~{R})-1,2,3-trimethoxy-10-methylsulfanyl-9-oxidanylidene-6,7-dihydro-5~{H}-benzo[a]heptalen-7-yl]ethanamide, CALCIUM ION, ... (12 entities in total)
• 機能のキーワード: microtubules, thiocolchicine, tubulin, tubulin-tyrosine ligase, structural protein
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 261968.55

構造登録者

Marangon, J.,Christodoulou, M.,Casagrande, F.,Tiana, G.,Dalla Via, L.,Aliverti, A.,Passarella, D.,Cappelletti, G.,Ricagno, S. (登録日: 2016-08-11, 公開日: 2016-09-21, 最終更新日: 2024-01-10)

主引用文献

Marangon, J.,Christodoulou, M.S.,Casagrande, F.V.,Tiana, G.,Dalla Via, L.,Aliverti, A.,Passarella, D.,Cappelletti, G.,Ricagno, S.
Tools for the rational design of bivalent microtubule-targeting drugs.
Biochem. Biophys. Res. Commun., 479:48-53, 2016

PubMed Abstract: Microtubule (MT) dynamic behaviour is an attractive drug target for chemotherapy, whose regulation by MT-stabilizing and destabilizing agents has been fruitfully applied in treating several types of cancers. MT-stabilizing agents are also emerging as potential remedies for neurodegenerative conditions, such as Alzheimer's and Parkinson's disease, although single-target drugs are not expected to fully cure these complex pathologies. Drug combination often displays enhanced efficacy with respect to mono-therapies. In particular, MT-targeting bivalent compounds (MTBCs) represent a promising class of molecules; however, surprisingly, the majority of MTBCs reported so far exhibit equal if not less efficacy than their building monomers. In order to shed light on MTBCs poor performance, we characterised through a set of complementary approaches thiocolchine (TH) and two bivalent TH-homodimers as prototype molecules. First, the binding affinities of these three molecules were assessed, then we obtained the crystallographic structure of a tubulin-TH complex. The binding affinities were interpreted in light of structural data and of molecular dynamics simulations. Finally, their effects on MT cytoskeleton and cell survival were validated on HeLa cells. The ensemble of these data provides chemical and structural considerations on how a successful rational design of MTBCs should be conceived.

PubMed: 27613098
DOI: 10.1016/j.bbrc.2016.09.022

実験手法

X-RAY DIFFRACTION (2.9 Å)