Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1392501 | Chemistry & Biology | 2010 | 10 Pages |
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 full-size imageDownload 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