5LP6

Crystal structure of Tubulin-Stathmin-TTL-Thiocolchicine Complex

Summary for 5LP6

• Entry DOI: 10.2210/pdb5lp6/pdb
• Descriptor: 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)
• Functional Keywords: microtubules, thiocolchicine, tubulin, tubulin-tyrosine ligase, structural protein
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 6
• Total formula weight: 261968.55

Authors

Marangon, J.,Christodoulou, M.,Casagrande, F.,Tiana, G.,Dalla Via, L.,Aliverti, A.,Passarella, D.,Cappelletti, G.,Ricagno, S. (deposition date: 2016-08-11, release date: 2016-09-21, Last modification date: 2024-01-10)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.9 Å)