Rare binding with amino acids

Coordination chemistry of RE(III) with amino acids has been attracting much interest since the early 1970s after the discovery that certain RE(III) ions could be used as probes of calcium ion binding sites in proteins and enzymes [118, 119], Since then, a large amount of work on the solution and structural chemistry of rare earth-amino acid complexes has been published. The solution studies involve all of the rare earth elements and 13 (Gly, Ala, Val, Leu, Phe, Met, Pro, Ser, Tyr, His, Lys, Trp, and Arg) of the 20 standard amino acids, and more than 100 of the RE(III)-amino acid complexes have been structurally characterized. This section will cover the synthetic, structural, and solution chemistry of these complexes. 

The simplest modification is to place a destabilizing amino acid at the N-terminal end according to the N-end rule (Varshavsky, 1992). This can be done by expressing the protein as a fusion protein, e.g. with maltose binding protein behind a cleavage site specific for a rare-cutting protease, such as factor Xq. In this case the N-terminal amino acid can be any amino acid except proline. 

Most mutations of p53 genes are somatic missense mutations involving amino acid substitutions in the DNA binding domain. The mutant forms of p53 are misfolded proteins with abnormal conformations and the inability to bind to DNA, or they are less stable. Individuals with the rare disorder Li-Fraumeni syndrome, (an autosomal dominant trait) have one mutated p5 > gene and one normal p53 gene. These individuals have increased susceptibility to many cancers, such as leukemia, breast carcinomas, soft-tissue sarcomas, brain tumors, and osteosarcomas. 

Nature attempts to simplify its chemical environment and has selected L-amino acids as the natural form. This has the saving feature that only one set of enzymes with binding sites for L-amino acids must be produced. However, D-amino acids do arise in nature from spontaneous isomerization of L-amino acids (see above) or from a very few sites in nature (the action of penicillin involves a structure that contains D-alanine, see below). While the enzymes that act on L-amino acids will almost never interact with D-amino acids and vice versa, there are rare examples of enzymes that interact with both isomers. In the latter case, the enzyme binding site must be ambidextrous and have extra features that accommodate both isomers. In other words, enzymes naturally show stereoselectivity and avoidance of stereochemical selection is an exception. 

The first such molecule was 4, 5 -bis(dithioarsolanyl)fluorescein (FlAsH) that binds with picomolar affinity to peptides or proteins containing appropriately spaced tetracysteines with the general sequence Cys-Cys-Xaa-Xaa-Cys-Cys in which Xaa is an amino acid other than cysteine [7]. Such tetracysteine motifs are very rare in naturally occurring proteins, so only the tagged protein is labeled... 

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