Tubulin ligands, binding sites

Crabtree, D.V., Ojima, I., Geng, X., and Adler, A.J. Tubulins in tbe primate retina Evidence that xanthophylls may be endogenous ligands for the paclitaxel-binding site, Bioorg. Med. Chem., 9,1967-1976, 2001. 

The route of taxanes was finally unveiled with the use of a covalent ligand of the taxane binding site [21], Cyclostreptin, abacterial natural product [46,47] with weak, but irreversible tubulin assembly activity and strong apparent binding affinity for the paclit-axel site, covalently labels both a residue placed in the lumenal site of paclitaxel Asn228 and a residue previously proposed to be in the external binding site Thr220 (Fig. 3a). 

The study of the tubulin-bound conformation of paclitaxel has resulted in a number of protein-ligand models, partially or fully based on the electron diffraction structure of aP-tubulin in paclitaxel-stabilized Zn2+-induced sheets [5, 12], Obviously, the nature of the paclitaxel binding site and the paclitaxel conformation in the binding site have key implications for the design of new MSA. A deep knowledge of the bioactive conformation would also help to explain how compounds as structurally diverse as the epothilones [48], discodermolide [49], and eleutherobin [50] have very similar mechanisms of action. 

Fig. 4 Diagram of the crystal structure of the T2R complex showing the binding sites of MT-destabilizing drugs (PDB entry 1Z2B) [13]. Protein subunits are represented as ribbons. RB3-SLD is colored orange, a-tubulin is purple, and p-tubulin is green. Small-molecule ligands are represented as spheres (vinblastine orange, colchicine red, GTP yellow, and GDP magenta). Colchicine binds to the p-subunit at the intradimer interface. Vinblastine binds at the interdimer interface...

Recent Advances Allow the Binding Sites of Tubulin Ligands to be Defined... 

They can be classified in two main classes (poly)macrocyclic molecules (e.g. vinblastine) and (mostly linear) pseudopeptides (e.g. dolastatin 10). Some ligands (e.g. phomopsin) have characteristics of both classes (Fig. 5). Whether the tubulin binding sites of these widely diverse molecules overlap or not remains to be established. Whatever the case, taken together these sites define the tubulin vinca domain [43]. 

The X-ray crystallographic analysis of T2R crystals soaked with vinblastine has revealed its binding site between the two tubulins of this short protofilament-like curved assembly (Fig. 6) [55]. It is equally contributed by the a-subunit of one tubulin and the [i-subuni I of the other. Vinblastine therefore belongs to the growing class of small molecules ligands known as interfacial inhibitors [58] these... 

The colchicine binding site in tubulin was initially identified using a colchicine derivative bearing a sulfhydryl group, permitting unambiguous orientation of the ligand in the electron density map [15]. We have also determined the structure of... 

The identification of the binding site location within tubulin, together with the clarification of the binding mode for some representative destabilizing compounds, opened new perspectives to modeling studies in this field, making the application possible not only of ligand-based, but also structure-based approaches. 

Chart 11 Potential interaction pattern of PTX in the P-tubulin binding site. Dashed lines represent potential hydrogen bonds between the ligand and the protein residues [46]... 

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