Calixarene-mediated protein assembly
McGovern, Róise Ella
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Solved the first crystal structure of a protein-calixarene complex (at 1.4 Angstrom resolution). The results provide exact structural information on the amino acid preference of the anionic p-sulfonatocalixarene (sclx4) for the lysine-rich cytochrome c.(1) This work featured on the front cover of Nature Chemistry (July 2012 issue). The rich class of structurally well-defined calixarenes have been studied for several decades and some of their water-soluble derivatives are well known for their complexation ability of various proteins.(2) However, despite great efforts no crystal structure could be obtained until now. The detailed data analysis of an NMR titration of 15N-labelled cytochrome c with the calixarene revealed the presence of two or more binding sites, with mM affinities. The results from both techniques agree on the binding epitopes and the prediction of at least two binding sites on the protein surface. A cytochrome c mutant was also co-crystallised with sclx4 for comparison and the large crystals were electrochemically characterised.(3) In order to further substantiate the potential of sclx4 as a protein surface binder, the crystal structures of the calixarene complexed to lysozyme in its native form and in a modified form were solved to 1.7 Angstrom and 2.2 Angstrom, respectively.(4) In the native form, the calixarene generates a tetrameric protein assembly and exhibits a preference for arginine. The structure of the modified protein complexed with sclx4 provides the first structural example of a synthetic molecule binding dimethyllysine. This interaction is significant as it resembles the naturally occurring aromatic protein cage, essential for gene expression. The results are important because the solved structures present valuable models for the structure-aided design of artificial receptors to target the protein surface. References (1) McGovern et al. Nat. Chem. 2012, 4, 527., (2) Perret et al. Chem.Comm. 2006, 2425., (3) McGovern et al. (Manuscript in preparation) 2014, (4) McGovern et al. (Submitted) 2014
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