5NJH

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

5NJH の概要

• エントリーDOI: 10.2210/pdb5njh/pdb
• 分子名称: Tubulin alpha-1B chain, Tubulin beta-2B chain, Stathmin-4, ... (10 entities in total)
• 機能のキーワード: tubulin, microtubules, microtubule targeting agents, antitumoural, resistance to chemotherapy, structural protein
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• 細胞内の位置: Cytoplasm, cytoskeleton: P81947 Q6B856; Golgi apparatus : P63043
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 264288.29

構造登録者

Sharma, A.,Calvo, G.S.,Prota, A.E.,Diaz, J.F.,Steinmetz, M.O. (登録日: 2017-03-28, 公開日: 2017-06-21, 最終更新日: 2024-01-17)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.394 Å)