کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1392501 | 983745 | 2010 | 10 صفحه PDF | دانلود رایگان |

SummaryConventional approaches to site mapping have so far failed to identify the laulimalide binding site on microtubules. Using mass shift perturbation analysis and data-directed docking, we demonstrate that laulimalide binds to the exterior of the microtubule on β-tubulin, in a region previously unknown to support ligand binding and well removed from the paclitaxel site. Shift maps for docetaxel and laulimalide are otherwise identical, indicating a common state of microtubule stability induced by occupancy of the distinct sites. The preferred binding mode highlights the penetration of the laulimalide side chain into a deep, narrow cavity through a unique conformation not strongly populated in solution, akin to a “striking cobra.” This mode supports the development of a pharmacophore model and reveals the importance of the C1–C15 axis in the macrocycle.
Graphical AbstractFigure optionsDownload high-quality image (320 K)Download as PowerPoint slideHighlights
► The laulimalide binding site exists on the exterior of β-tubulin in microtubules
► The laulimalide binding mode is characterized to support further analog development
► Combining mass shift perturbation and data-directed docking represents a powerful method for protein-ligand mapping
Journal: - Volume 17, Issue 7, 30 July 2010, Pages 725–734