Complement protein binding site

Methods that utilize structural data of the target, generally identified by protein crystallography, to look for molecules that complement the binding site through favorable protein-ligand interactions (protein structure-based VS or SBVS). 

A natural product s bioactivity is often due to a defined shape that complements the binding site of a protein. Meggers and co-workers have demonstrated that simple organometallic scaffolds can be substituted for structurally more complicated natural products in binding at a target protein s active site <2006AGE1580>. A ruthenium complex 41 was synthesized to mimic the shape of the alkaloid staurosporine 42, a potent inhibitor of protein kinase Pim-1. 

Lanthanides have been used as substitutes for calcium in calcium binding proteins since the early days in NMR [155,156]. Remarkable information was obtained on systems such as Yb(III)-substituted parvalbumin (which contains a typical calcium binding site called EF-hand [157,158]) from ID spectroscopy alone [159-164], later complemented by 2D spectroscopy [165]. More recently, pseudocontact shifts and longitudinal proton relaxation times have been used to... 

Bischoff S, Leonhard S, Reymann N et al (1999) Spatial distribution of GABAb R1 receptor mRNA and binding sites in the rat brain. J Comp Neurol 412 1-16 Blein S, Ginham R, Uhrin D et al (2004) Structural analysis of the complement control protein (CCP) modules of GABAb receptor la. J Biol Chem 279 48292-306 Bockaert J, Pin J-P (1999) Molecular tinkering of G-protein-coupled receptors an evolutionary success. EMBO J 18 1723-9... 

To complement the ligands view on affinity and selectivity, it would be desirable to use the information about the nature of the binding sites contained in the three-dimensional (3D) structures of the targets. Traditionally, this has been done by visual inspection of the protein structures. However, this is error prone, as it is too easy to overlook an important difference, or to identify a potential source of selectivity which cannot be confirmed experimentally. 

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