5NJH

Triazolopyrimidines stabilize microtubules by binding to the vinca inhibitor site of tubulin

Summary for 5NJH

• Entry DOI: 10.2210/pdb5njh/pdb
• Descriptor: Tubulin alpha-1B chain, Tubulin beta-2B chain, Stathmin-4, ... (10 entities in total)
• Functional Keywords: tubulin, microtubules, microtubule targeting agents, antitumoural, resistance to chemotherapy, structural protein
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cytoplasm, cytoskeleton: P81947 Q6B856; Golgi apparatus : P63043
• Total number of polymer chains: 6
• Total formula weight: 264288.29

Authors

Sharma, A.,Calvo, G.S.,Prota, A.E.,Diaz, J.F.,Steinmetz, M.O. (deposition date: 2017-03-28, release date: 2017-06-21, Last modification date: 2024-01-17)

Primary citation

Saez-Calvo, G.,Sharma, A.,Balaguer, F.A.,Barasoain, I.,Rodriguez-Salarichs, J.,Olieric, N.,Munoz-Hernandez, H.,Berbis, M.A.,Wendeborn, S.,Penalva, M.A.,Matesanz, R.,Canales, A.,Prota, A.E.,Jimenez-Barbero, J.,Andreu, J.M.,Lamberth, C.,Steinmetz, M.O.,Diaz, J.F.
Triazolopyrimidines Are Microtubule-Stabilizing Agents that Bind the Vinca Inhibitor Site of Tubulin.
Cell Chem Biol, 24:737-750.e6, 2017

PubMed Abstract: Microtubule-targeting agents (MTAs) are some of the clinically most successful anti-cancer drugs. Unfortunately, instances of multidrug resistances to MTA have been reported, which highlights the need for developing MTAs with different mechanistic properties. One less explored class of MTAs are [1,2,4]triazolo[1,5-a]pyrimidines (TPs). These cytotoxic compounds are microtubule-stabilizing agents that inexplicably bind to vinblastine binding site on tubulin, which is typically targeted by microtubule-destabilizing agents. Here we used cellular, biochemical, and structural biology approaches to address this apparent discrepancy. Our results establish TPs as vinca-site microtubule-stabilizing agents that promote longitudinal tubulin contacts in microtubules, in contrast to classical microtubule-stabilizing agents that primarily promote lateral contacts. Additionally we observe that TPs studied here are not affected by p-glycoprotein overexpression, and suggest that TPs are promising ligands against multidrug-resistant cancer cells.

PubMed: 28579361
DOI: 10.1016/j.chembiol.2017.05.016

Experimental method

X-RAY DIFFRACTION (2.394 Å)