用于微管蛋白结合紫杉醇构象的旋转回波双共振核磁共振距离测量。
Rotational-echo double-resonance NMR distance measurements for the tubulin-bound Paclitaxel conformation.
作者信息
Paik Younkee, Yang Chao, Metaferia Belhu, Tang Shoubin, Bane Susan, Ravindra Rudravajhala, Shanker Natasha, Alcaraz Ana A, Johnson Scott A, Schaefer Jacob, O'Connor Robert D, Cegelski Lynette, Snyder James P, Kingston David G I
机构信息
Department of Chemistry, M/C 0212, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA.
出版信息
J Am Chem Soc. 2007 Jan 17;129(2):361-70. doi: 10.1021/ja0656604.
Abstract
The important anticancer drug Taxol (paclitaxel, PTX) owes its unique activity to its ability to bind to tubulin in a stoichiometric ratio and promote its assembly into microtubules. The conformation of the microtubule-bound drug has been the focus of numerous research efforts, since the inability of polymerized tubulin to form crystals precludes structure proof by X-ray crystallography. Likewise, although the alpha,beta-tubulin dimer structure has been solved by electron crystallography, the 3.7 A resolution is too low to permit direct determination of either ligand conformation or binding pose. In this article, we present experimental results from 2H{19F} REDOR NMR that provide direct confirmation that paclitaxel adopts a T-shaped conformation when it is bound to tubulin.
摘要
重要的抗癌药物紫杉醇（paclitaxel，PTX）因其能够以化学计量比与微管蛋白结合并促进其组装成微管而具有独特活性。由于聚合的微管蛋白无法形成晶体，从而排除了通过X射线晶体学确定结构的可能性，因此与微管结合的药物构象一直是众多研究工作的重点。同样，尽管α,β-微管蛋白二聚体结构已通过电子晶体学解析，但3.7埃的分辨率太低，无法直接确定配体构象或结合姿态。在本文中，我们展示了2H{19F} REDOR NMR的实验结果，这些结果直接证实了紫杉醇与微管蛋白结合时采用T形构象。
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本文引用的文献
1
Recent advances in the new generation taxane anticancer agents.新一代紫杉烷类抗癌药物的最新进展。
Med Chem. 2005 Mar;1(2):125-39. doi: 10.2174/1573406053175292.
2
The T-Taxol conformation.T-紫杉醇构象
J Med Chem. 2006 Apr 20;49(8):2478-88. doi: 10.1021/jm051119r.
3
Paclitaxel-resistant cells have a mutation in the paclitaxel-binding region of beta-tubulin (Asp26Glu) and less stable microtubules.耐紫杉醇细胞在β-微管蛋白的紫杉醇结合区域存在突变（天冬氨酸26突变为谷氨酸），且微管稳定性较低。
Mol Cancer Ther. 2006 Feb;5(2):270-8. doi: 10.1158/1535-7163.MCT-05-0190.
4
T-Taxol and the electron crystallographic density in beta-tubulin.T-紫杉醇与β-微管蛋白中的电子晶体学密度
Org Lett. 2005 Dec 8;7(25):5549-52. doi: 10.1021/ol051780p.
5
The INPHARMA method: protein-mediated interligand NOEs for pharmacophore mapping.INPHARMA方法：用于药效团映射的蛋白质介导的配体间核Overhauser效应
Angew Chem Int Ed Engl. 2005 Jul 4;44(27):4172-5. doi: 10.1002/anie.200500503.
6
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7
Recent progress in structure activity relationship and mechanistic studies of taxol analogues.紫杉醇类似物的构效关系及作用机制研究的最新进展
Mini Rev Med Chem. 2005 Jan;5(1):1-12. doi: 10.2174/1389557053402837.
8
The taxol pharmacophore and the T-taxol bridging principle.紫杉醇药效基团与T-紫杉醇桥连原理。
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J Med Chem. 2004 Nov 18;47(24):5937-44. doi: 10.1021/jm0497996.
10
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