Figure 5.

Peloruside A binding site in β-tubulin. (A) Global view of the exterior macrolide binding site on β-tubulin relative to the taxoid binding site on β-tubulin. Protein structure represented as a cartoon model using PBD entry 1JFF, where α-tubulin is colored cyan and β-tubulin pale green. Peloruside A is shown in blue spheres and taxol in red spheres. Exchangeable nucleotide (GDP) is shown as yellow sticks. (B) Closeup view of the binding site showing the position of the Pel^r mutations. Binding models showing details of the binding modes for peloruside A (left), based on a reanalysis of docking results and laulimalide (right), adapted from Bennett 2010. Protein structure is rendered in cartoon, highlighting only the binding domain on β-tubulin, and based on PBD file 1JFF as the starting model. Colored secondary structure (orange, yellow, red) represent peptides marking the macrolide binding site by mass shift analysis, from the original determinations of the site (Huzil 2008, Bennett 2010). Ligand structures show only carbon atoms (green) and oxygen atoms (red). Note that both structures orient their long side chains into the cleft defined by in part by A296, R306, N337 and Y340.