EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	An evolution-conserved allosteric network in human tubulin governs paclitaxel efficacy.
ジャーナル・号・ページ	Nat Chem Biol, Year 2026
掲載日	2026年4月15日
著者	Jingyi Luo / Chen Jing Khoo / Weixin Chen / Zheng Liu / Boxuan Li / Wei Sin Lau / Xiang David Li / Shih-Chieh Ti /
PubMed 要旨	Tubulin-targeting agents such as paclitaxel have been a cornerstone of cancer treatment. However, the molecular basis by which prognosis-associated tubulin isotypes and mutations (that is, variants) ...Tubulin-targeting agents such as paclitaxel have been a cornerstone of cancer treatment. However, the molecular basis by which prognosis-associated tubulin isotypes and mutations (that is, variants) affect drug efficacy remains unclear. Here we reveal that evolutionarily conserved tubulin residues modulate the allosteric network to determine paclitaxel efficacy. The paclitaxel resistance of human β3-tubulin depends on a residue distant from the taxane-binding pocket. The ~2.3 Å-resolution cryo-EM microtubule reconstructions demonstrate that the paclitaxel-sensitizing tubulin mutation induces allostery at the paclitaxel-binding site, intertubulin interactions and nucleotide-binding pockets. In particular, the reoriented guanine triphosphate (GTP)-hydrolyzing catalytic α-tubulin E254 residue enhances the GTP cap, reducing the catastrophe frequency of dynamic microtubules. Examining genome-edited cancer cells with the paclitaxel-sensitized mutant β3-tubulin indicates that the affinities of tubulin variants for paclitaxel determine drug efficacy. Our findings provide mechanistic insights into the development of new tubulin-targeting therapeutics not only for cancer but also for tubulinopathies associated with mutations in specific tubulin isotypes.
リンク	Nat Chem Biol / PubMed:41986561
手法	EM (単粒子)
解像度	2.26 - 2.48 Å
構造データ	65885 9wd7 EMDB-65885, PDB-9wd7: GMPCPP-stabilizsd human alpha1A/beta3 microtubule 手法: EM (単粒子) / 解像度: 2.34 Å 65886 9wd9 EMDB-65886, PDB-9wd9: GMPCPP-stabilized human alpha1A/beta3 S239C microtubule 手法: EM (単粒子) / 解像度: 2.26 Å 65887 9wda EMDB-65887, PDB-9wda: Paclitaxel/GMPCPP-stabilized human alpha1A/beta3 microtubule 手法: EM (単粒子) / 解像度: 2.35 Å 65888 9wdb EMDB-65888, PDB-9wdb: Paclitaxel/GMPCPP-stabilized human alpha1A/beta3 S239C microtubule 手法: EM (単粒子) / 解像度: 2.39 Å 68133 22aj EMDB-68133, PDB-22aj: GDP human alpha1A/beta3 S239C microtubule 手法: EM (単粒子) / 解像度: 2.48 Å 68134 22ak EMDB-68134, PDB-22ak: GDP human alpha1A/beta3 microtubule 手法: EM (単粒子) / 解像度: 2.41 Å
化合物	ChemComp-MG: Unknown entry ChemComp-GDP: GUANOSINE-5'-DIPHOSPHATE / GDP, エネルギー貯蔵分子YM ChemComp-GTP: GUANOSINE-5'-TRIPHOSPHATE / GTP, エネルギー貯蔵分子YM ChemComp-G2P: PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER / GMP-CPP, エネルギー貯蔵分子類似体YM ChemComp-TA1: TAXOL / 薬剤, 化学療法薬YM
由来	homo sapiens (ヒト)
キーワード	STRUCTURAL PROTEIN / Cytoskeleton / microtubules / human tubulin isotypes / paclitaxel