7ogn | pdb_00007ogn
Crystal structure of T2R-TTL -mebendazole complex
Structural highlights
FunctionTBA1B_BOVIN Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain. Publication Abstract from PubMedMicrotubule targeting agents (MTAs) have been exploited mainly as anti-cancer drugs because of their impact on cellular division and angiogenesis. Additionally, microtubules (MTs) are key structures for intracellular transport, which is frequently hijacked during viral infection. We have analyzed the antiviral activity of clinically used MTAs in the infection of DNA and RNA viruses, including SARS-CoV-2, to find that MT destabilizer agents show a higher impact than stabilizers in the viral infections tested, and FDA-approved anti-helminthic benzimidazoles were among the most active compounds. In order to understand the reasons for the observed antiviral activity, we studied the impact of these compounds in motor proteins-mediated intracellular transport. To do so, we used labeled peptide tools, finding that clinically available MTAs impaired the movement linked to MT motors in living cells. However, their effect on viral infection lacked a clear correlation to their effect in motor-mediated transport, denoting the complex use of the cytoskeleton by viruses. Finally, we further delved into the molecular mechanism of action of Mebendazole by combining biochemical and structural studies to obtain crystallographic high-resolution information of the Mebendazole-tubulin complex, which provided insights into the mechanisms of differential toxicity between helminths and mammalians. Effect of Clinically Used Microtubule Targeting Drugs on Viral Infection and Transport Function.,Oliva MA, Tosat-Bitrian C, Barrado-Gil L, Bonato F, Galindo I, Garaigorta U, Alvarez-Bernad B, Paris-Ogayar R, Lucena-Agell D, Gimenez-Abian JF, Garcia-Dorival I, Urquiza J, Gastaminza P, Diaz JF, Palomo V, Alonso C Int J Mol Sci. 2022 Mar 22;23(7):3448. doi: 10.3390/ijms23073448. PMID:35408808[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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