Proteins crystallization, small molecule drug

Hosfield, D., Palan, J., Hilgers, M., Scheibe, D., McRee, D. E., and Stevens, R. C. 2003. A fully integrated protein crystallization platform for small-molecule drug discovery. J. Struct. Biol. 142 207-217. 

Small molecules modulating microtubule assembly have played major roles as tools in microtubule research, in a manner closely related to their chemotherapeutic interest [1], Tubulin was first purified in the last century as the colchicine-binding protein proposed to be the subunit of cellular microtubules [2], More recently, a colchicine derivative was employed to help crystallization and determine the structure of tubulin by X-ray diffraction [3], The colchicine, vinblastine [4] and paclitaxel [5] sites are main drug binding sites of tubulin, to which many other substances bind. The discovery of microtubule stabilization by paclitaxel [6] prompted its clinical development [7] and a burst of research on new MSAs, as well as the generalized use of paclitaxel or docetaxel as convenient reagents to assemble (see Fig. 1), stabilize or detect microtubules in the laboratory. One example is the development... 

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...

In order to form a crystal, molecules must aggregate in an orderly manner. This implies that intermolecular interactions have occurred in specific ways. It therefore follows that the crystal structure per se contains information on preferred modes of binding between the molecules in the crystalline state. In this Chapter we show how information on the most likely stereochemistries of interactions between functional groups in different molecules can be extracted from the three-dimensional coordinates of atoms listed in reports of crystal structure determinations. Three-dimensional structural data on binding stereochemistry may also be obtained from X-ray diffraction studies of the binding of small molecules to crystalline proteins and other macromolecules. These two types of information can be used, for example, to predict how drugs will interact with their biological receptors. 

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