5YZ3

Crystal structure of T2R-TTL-28 complex

5YZ3 の概要

• エントリーDOI: 10.2210/pdb5yz3/pdb
• 分子名称: Tubulin alpha-1B chain, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, N-[4-(diethylamino)phenyl]-4H-pyrrolo[2,3-d][1,3]thiazole-5-carboxamide, ... (15 entities in total)
• 機能のキーワード: tubulin, complex, structural protein-inhibitor complex, structural protein, cell cycle
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 264974.89

構造登録者

Yu, Y.,Chen, Q. (登録日: 2017-12-12, 公開日: 2018-10-24, 最終更新日: 2023-11-22)

主引用文献

Ning, N.,Yu, Y.,Wu, M.,Zhang, R.,Zhang, T.,Zhu, C.,Huang, L.,Yun, C.H.,Benes, C.H.,Zhang, J.,Deng, X.,Chen, Q.,Ren, R.
A Novel Microtubule Inhibitor Overcomes Multidrug Resistance in Tumors.
Cancer Res., 78:5949-5957, 2018

PubMed Abstract: Microtubule inhibitors as chemotherapeutic drugs are widely used for cancer treatment. However, the development of multidrug resistance (MDR) in cancer is a major challenge for microtubule inhibitors in their clinical implementation. From a high-throughput drug screen using cells transformed by oncogenic RAS, we identify a lead heteroaryl amide compound that blocks cell proliferation. Analysis of the structure-activity relationship indicated that this series of scaffolds (exemplified by MP-HJ-1b) represents a potent inhibitor of tumor cell growth. MP-HJ-1b showed activities against a panel of more than 1,000 human cancer cell lines with a wide variety of tissue origins. This compound depolymerized microtubules and affected spindle formation. It also induced the spike-like conformation of microtubules and , which is different from typical microtubule modulators. Structural analysis revealed that this series of compounds bound the colchicine pocket at the intra-dimer interface, although mostly not overlapping with colchicine binding. MP-HJ-1b displayed favorable pharmacological properties for overcoming tumor MDR, both and Taken together, our data reveal a novel scaffold represented by MP-HJ-1b that can be developed as a cancer therapeutic against tumors with MDR. Paclitaxel is a widely used chemotherapeutic drug in patients with multiple types of cancer. However, resistance to paclitaxel is a challenge. This study describes a novel class of microtubule inhibitors with the ability to circumvent multidrug resistance across multiple tumor cell lines. .

PubMed: 30135190
DOI: 10.1158/0008-5472.CAN-18-0455

実験手法

X-RAY DIFFRACTION (2.545 Å)