Finger coordination

Figure 39-14. Zinc fingers are a series of repeated domains (two to nine) in which each is centered on a tetrahedral coordination with zinc. In the case of TFIIIA, the coordination is provided by a pair of cysteine residues (C) separated by 12-13 amino acids from a pair of histidine (H) residues. In other zinc finger proteins, the second pair also consists of C residues. Zinc fingers bind in the major groove, with adjacent fingers making contact with 5 bp along the same face of the helix.

Varying ratios of the ligands 7V-(2-thiophenyl)-2,5-dimethylpyrrole and V-methylimidazole were used to form tetrahedral zinc complexes with S4, S3N, and S2N2 coordination spheres. X-ray structural analyses and IR spectra were recorded for all compounds and the relevance to zinc finger proteins was discussed. The comparison to cobalt and cadmium structures showed only minor differences, supporting the theory that changes on substituting these metals into zinc proteins would be minor.538... 

Zinc is a constituent of over 300 enzymes with much research into the coordination of zinc to the protein backbone, and how its chemistry is modulated by the donor set and environment.2 As well as the Lewis acid catalysis properties in enzymes, the structural role in zinc finger proteins has been a major area of research since the late 1990s. A number of reviews on zinc physiology, enzymology, and proteins in general have been published.978-981 There is extensive analysis available to classify the mononuclear sites in zinc proteins and identification of structural relationships of the extended environment.982,983... 

Fig. 9.1. Left panel A model zinc finger obtained using the second domain of the transcription factor IIIA. The zinc ion (gray sphere) is coordinated tetrahedrally by two histidine (H) and two cysteine (C) residues. Right panel Results showing the free energy change for displacing Zn2+ by other comparable ions Fe2+ and Co2+ from different binding motifs CCHH, CCHC, and CCCC, respectively...

Fig. 1.6. Binding domain to DNA. ERs contain two structures called zinc fingers, typical of proteins that interact with DNA. One zinc atom forms four links of coordination with four cysteine residues of the protein structure, which occupy nearby positions, thus leaving a loop of some 15 to 22 aminoacids. The zinc fingers of the receptor are capable of interacting with specific sequences of DNA, the hormone response elements, with which they establish hydrogen bridges and form stable structures...

The zinc fingers are common structures among the transcription factors. Nevertheless, the coordination with zinc is more frequently produced between two histidine residues and two neighboring cysteines than when it is among four cysteine residues, as occurs in the nuclear hormone receptors. The zinc fingers provide an optimum architecture for the mutual recognition between specific sequences of amino acids and nucleotides. In the case of the nuclear receptors, the interaction occurs between particular amino acids of the DBD and guanine residues of the DNA sequence (Fig. 1.7). 

Figure 12.14 (Left) Schematic representation of tandemly repeated zinc finger motif with their tetrahedrally coordinated Zn2+ ions. Conserved amino acids are labelled, and the most probable DNA-binding side chains are indicated by balls (from Klug and Rhodes, 1988). (Right) A ribbon diagram of a single zinc finger motif in a ribbon diagram representation. (From Voet and Voet, 2004. Reproduced with permission from John Wiley Sons., Inc.)...

Auld, D.S. (2001) Zinc coordination sphere in biochemical zinc sites, BioMetals, 14, 271-313. Klug, A. and Rhodes, D. (1988) Zinc fingers a novel protein motif for nucleic acid recognition, TIBS, 12, 464-469. 

A considerable number of transcription factors have reactive cysteine residues, which enable them to respond to the redox conditions in the cell. Since cadmium perturbs redox homeostasis, it can affect this class of transcription factors. If cadmium can displace the tetra-coordinate zinc atoms in zinc finger-containing transcription factors, it will affect them as well. Many of the pathways involving activation and inactivation of transcription factors involve kinases and phosphatases, themselves under the intricate control of calcium fluxes. It is therefore no surprise that cadmium will exert effects on the activity of transcription factors, the activation of proto-oncogenes, and thereby on gene expression (Figure 20.8i and i ). 

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