5O7A

Quinolin-6-yloxyacetamides are microtubule destabilizing agents that bind to the colchicine site of tubulin

Summary for 5O7A

• Entry DOI: 10.2210/pdb5o7a/pdb
• Descriptor: Tubulin alpha-1B chain, Tubulin beta-2B chain, Stathmin-4, ... (10 entities in total)
• Functional Keywords: microtubules, tubulin, colchicine, quinolin-6-yloxyacetamides, motor protein
• Biological source: Rattus norvegicus (Norway Rat); More
• Cellular location: Cytoplasm, cytoskeleton: P81947 Q6B856; Golgi apparatus : P63043
• Total number of polymer chains: 6
• Total formula weight: 264877.29

Authors

Sharma, A.,Olieric, N.,Steinmetz, M.O. (deposition date: 2017-06-08, release date: 2017-07-05, Last modification date: 2024-05-08)

Primary citation

Sharma, A.,Saez-Calvo, G.,Olieric, N.,de Asis Balaguer, F.,Barasoain, I.,Lamberth, C.,Diaz, J.F.,Steinmetz, M.O.
Quinolin-6-Yloxyacetamides Are Microtubule Destabilizing Agents That Bind to the Colchicine Site of Tubulin.
Int J Mol Sci, 18:-, 2017

PubMed Abstract: Quinolin-6-yloxyacetamides (QAs) are a chemical class of tubulin polymerization inhibitors that were initially identified as fungicides. Here, we report that QAs are potent anti-proliferative agents against human cancer cells including ones that are drug-resistant. QAs act by disrupting the microtubule cytoskeleton and by causing severe mitotic defects. We further demonstrate that QAs inhibit tubulin polymerization in vitro. The high resolution crystal structure of the tubulin-QA complex revealed that QAs bind to the colchicine site on tubulin, which is targeted by microtubule-destabilizing agents such as colchicine and nocodazole. Together, our data establish QAs as colchicine-site ligands and explain the molecular mechanism of microtubule destabilization by this class of compounds. They further extend our structural knowledge on antitubulin agents and thus should aid in the development of new strategies for the rational design of ligands against multidrug-resistant cancer cells.

PubMed: 28640209
DOI: 10.3390/ijms18071336

Experimental method

X-RAY DIFFRACTION (2.495 Å)