7CEK

Crystal structure of T2R-TTL-BML-284 complex

7CEK の概要

• エントリーDOI: 10.2210/pdb7cek/pdb
• 分子名称: Tubulin alpha-1B chain, N4-(1,3-benzodioxol-5-ylmethyl)-6-(3-methoxyphenyl)pyrimidine-2,4-diamine, CHLORIDE ION, ... (13 entities in total)
• 機能のキーワード: tubulin inhibitor, tublin, structural protein-inhibitor complex
• 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: 265116.35

構造登録者

Chen, L.J.,Chen, Q.,Yu, Y.,Yang, J.H. (登録日: 2020-06-23, 公開日: 2021-06-23, 最終更新日: 2023-11-29)

主引用文献

Yang, J.,Li, Y.,Qiu, Q.,Wang, R.,Yan, W.,Yu, Y.,Niu, L.,Pei, H.,Wei, H.,Ouyang, L.,Ye, H.,Xu, D.,Wei, Y.,Chen, Q.,Chen, L.
Small Molecules Promote Selective Denaturation and Degradation of Tubulin Heterodimers through a Low-Barrier Hydrogen Bond.
J.Med.Chem., 65:9159-9173, 2022

PubMed Abstract: Here, we report a novel mechanism to selectively degrade target proteins. 3-(3-Phenoxybenzyl)amino-β-carboline (PAC), a tubulin inhibitor, promotes selective degradation of αβ-tubulin heterodimers. Biochemical studies have revealed that PAC specifically denatures tubulin, making it prone to aggregation that predisposes it to ubiquitinylation and then degradation. The degradation is mediated by a single hydrogen bond formed between the pyridine nitrogen of PAC and βGlu198, which is identified as a low-barrier hydrogen bond (LBHB). In contrast, another two tubulin inhibitors that only form normal hydrogen bonds with βGlu198 exhibit no degradation effect. Thus, the LBHB accounts for the degradation. We then screened for compounds capable of forming an LBHB with βGlu198 and demonstrated that BML284, a Wnt signaling activator, also promotes tubulin heterodimer degradation through the LBHB. Our study provided a unique example of LBHB function and identified a novel approach to obtain tubulin degraders.

PubMed: 35762925
DOI: 10.1021/acs.jmedchem.2c00379

実験手法

X-RAY DIFFRACTION (2.696 Å)