Histidine structural diversity

In SELEX, multiple rounds of in vitro transcription of random nucleic acid pools, affinity selection, and RT-PCR are performed, thus giving rise to exponential amplification of the selected molecules. The principle underlying SELEX is schematically depicted in Figure 1. After several selection cycles, the binders can subsequently be cloned and sequenced and then characterized. In SELEX, genotype and phenotype are simultaneously represented by the same RNA molecule, since it exerts its function through its three-dimensional structure, which is in turn determined by its nucleotide sequence. The chemical and functional diversity of RNA can be further increased by addition of cofactors such as histidine (Roth and Breaker, 1998) and divalent cations (Tarasow et al, 1997) to the selection. 

Based on its amino acid sequence and three-dimensional structure, 2,3QP can be classified within the cupin superfamiliy. This superfamiliy includes functionally diverse proteins that are found in archaea, eubacteria, and eukaryota. Structural information shows that they contain a motif of six antiparallel /3-strands located within a conserved /3-barrel structure. The structure of gemin, which is a 16kDa Mn-containing oxalate oxidase, can be superimposed on the N-terminal domain of 2,3QD with an rms deviation of 1.8 A for 91 Ca atoms. One can see in the superposition that the Mn site of germin formed by three histidines, a glutamate, and two water molecules matches with the copper site of 2,3QD. 

The structures shown in Figures 1 and 2 illustrate several general structural themes that facilitate rationalization of functional diversity. Exclusive cysteinyl ligation is generally observed in centers that function purely in electron transfer roles. Histidine, aspartate, serine, or backbone amide N ligation at a unique Fe site are occasionally encountered in clusters that function in electron transport and serve to modify redox potentiaH and gate electron transport,or facilitate coupling of proton and electron transport. 

Berkessel et al. took a diversity-based approach to the discovery of functional models for GOase 42). Based on the known coordination pattern of the catalytically active copper ion (X-ray crystal structure of GOase from Dactylium dendroides, schematically in Scheme 12), the peptide/peptoid library 29 (Scheme 13) was designed. In this library, the Gly-D-Pro-turn positions the four amino acids X -X such that they can coordinate a copper ion. The four positions X X were occupied, in a combinatorial manner, by either histidine, tyrosine, the Cys22s-Tyr272-model mod-Cys (30), and in particular the TEMPO-derived amino acid TOAC (31) (Scheme 13). Thus, the TOAC-derived library comprised a total of 81 decapeptides, and it was synthesized... 

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