Tubulin binding sites

Llanos, R., Chevrier, V., Ronjat, M., Meurer-Grob, P., Martinez, P., Frank, R., Bomens, M., Wade, R. H., Wehland.J., andjob, D. (1999). Tubulin binding sites on y-tubulin Identification and molecular characterization. Biochemistry 38, 15712-15720. 

Thus, the fluorine probe approach has proved useful for the conformational analysis of paclitaxel and taxoids in connection with the determination of possible bioactive conformations.77 The previously unrecognized conformer C might be the molecular structure first recognized by the P-tubulin binding site on microtubules. 

The natural products eleutherobin (1), epothilone (23), paditaxel (24), nonataxel (25), and discodermolide (26) (Figure 6) show a similar mode of action. Furthermore, competitive inhibition of paditaxel binding to microtubules by epothilone, eleutherobin, and discodermolide is observed, and so a common pharmacophore and the existence of a common tubulin binding site are therefore strongly suggested [15]. The identification of comparable structural characteristics is complicated, since conformations established by NMR spectroscopy or X-ray structure analysis do not necessarily correspond to the binding conformations [16]-... 

Indeed, before 2000, single conformers had been basically considered, although it was possible that the multiple torsional degrees of freedom of these molecules would produce a complex multidimensional energy surface, and therefore a variety of putative 3D geometries capable of interacting with the tubulin binding site [62, 63], Numerous research teams pursued different indirect approaches to the pharmacophore... 

Computational studies have been of paramount importance in order to integrate the results of the experimental studies indicated above with the electron crystallographic data known. According to Snyder and co-workers, a satisfactory and experimentally verifiable model of the tubulin-binding site and of the conformation of paclitaxel has been obtained by computational methods on the first electron crystallographic model. In this context, a new paclitaxel conformer, T-Taxol (Fig. 10c), was proposed [59, 81, 82],... 

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]. 

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]... 

Altered tubulin binding site Detoxification and sequestration Detoxification... 

Maccari L, Manetti F, Corelli F, et al. 3D QSAR studies for the (3-tubulin binding site of microtubule-stabilizing anticancer agents (MSAAs). A pseudoreceptor model for taxanes based on the experimental structure of tubulin. II Farmaco 2003 58 659-668. 

Islam MN, Song Y, Iskander MN. Investigation of structural requirements of anticancer activity at the paclitaxel/tubulin binding site using CoMFAand CoMSIA. J Mol Graph Model 2003 21 263-272. 

FIGURE 1 4 (See color insert following page 172.) Native contact maps for kinesin dimer (left) and the interface between the kinesin and tubulin binding site (right). The neck-linker zipper contacts that play several important roles for the kinesin function are enclosed in the circles (the green circles for the MT-bound head, and the yellow circles for the tethered head). 

While the conformational transition of neck-linker occurs with the timescale of Tp, the tethered head in ADP state undergoes diffusion on the MT surface. The conformational transition of neck-linker in the MT-bound head affects the diffusional motion of the tethered head that searches for the next tubulin binding site in a time-dependent fashion. The diffusion of the tethered head is rectified by the conformational change of the neck-linker of the MT-bound head. 

I. Ojima who suggested the PTX-NY conformer, in which the C-13 side chain is proposed to adopt a different conformation and an alternative hydrogen-bonding pattern in the tubulin binding site [8]. The two conformers were compared to show that only T-Taxol fits the PTX-derived electron crystallographic density [9]. 

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