Zinc, ligands

Fig. 10. Pharmacophores for angiotension-converting enzyme. Distances in nm. (a) The stmcture of a semirigid inhibitor and distances between essential atoms from which one pharmacophore was derived (79). (b) In another pharmacophore, atom 1 is a potential zinc ligand (sulfhydryl or carboxylate oxygen), atom 2 is a neutral hydrogen bond acceptor, atom 3 is an anion (deprotonated sulfur or charged oxygen), atom 4 indicates the direction of a hydrogen bond to atom two, and atom 5 is the central atom of a carboxylate, sulfate, or phosphate of which atom 3 is an oxygen, or atom 5 is an unsaturated carbon when atom 3 is a deprotonated sulfur. The angle 1- -2- -3- -4 is —135 to —180° or 135 to 180°, and 1- -2- -3- -5 is —90 to 90°.

This is precisely where the catalytically essential zinc atom is found. This zinc atom is located precisely at this switch point, where it is firmly anchored to the protein by three side-chain ligands, His 69, Glu 72, and His 196 (Figure 4.20). The last residue of p strand 3 is residue 66, so the two zinc ligands His 69 and Glu 72 are at the beginning of the loop region that connects this p strand with its corresponding a helix. The last residue of p strand 5 is the third zinc ligand. His 196. 

The 12 residues between the second cysteine zinc ligand and the first histidine ligand of the classic zinc finger motif form the "finger region". Structurally, this region comprises the second p strand, the N-terminal half of the helix and the two residues that form the turn between the p strand and the helix. This is the region of the polypeptide chain that forms the main interaction area with DNA and these interactions are both sequence specific. 

The two zinc ions fulfill important but different functions in the DNA-binding domains. The first zinc ion is important for DNA-bindlng because it properly positions the recognition helix the last two cysteine zinc ligands are part of this helix. The second zinc ion is important for dimerization since the five-residue loop between the first two cysteine zinc ligands is the main component of the dimer interaction area. 

The world of zinc-containing DNA-binding proteins is by no means exhausted by these three subfamilies. Several other subfamilies are already known with different three-dimensional structures and different sequence patterns of cysteine and histidine residues that form the zinc ligands. Further subfamilies may well be discovered as the genomes of different species are sequenced whether or not any fundamentally new principles for DNA-protein recognition will be discovered amongst these new subfamilies remains to be seen. 

Other reagents have been developed in which one of the zinc ligands is an oxy anion. Compounds with trifluoroacetate anions are prepared by protonolysis of C2H5 or CH2I groups on zinc.179... 

The ligand 6,13-dimethyl-l,4,8,ll-tetra-azacyclotetradecane-6,13-diamine coordinates as a hexadentate ligand to zinc in neutral aqueous solution. Potentiometric titrations were used to determine the stability constant for formation. The pXa values were determined for five of the six possible protonation steps of the hexamine (2.9, 5.5, 6.3, 9.9 and 11.0).697 Studies of the syn and anti isomers of 6,13-dimethyl-1,4,8, ll-tetraazacyclotetradecane-6,13-diamine reveal that they offer different shapes for metal binding, which is reflected in the stability constants for 1 1 zinc ligand ratio complexes. The selectivity of binding to the zinc ion compared to the cadmium(II) ion by both isomers is significant.698... 

Zinc ligands are soluble in neutral and acidic solutions, so that zinc is readily transported in most natural waters (USEPA 1980, 1987), but zinc oxide, the compound most commonly used in industry, has a low solubility in most solvents (Elinder 1986). Zinc mobility in aquatic ecosystems is a function of the composition of suspended and bed sediments, dissolved and particulate iron and manganese concentrations, pH, salinity, concentrations of complexing ligands, and the concentration of zinc (USEPA 1980). In freshwater, zinc is most soluble at low pH and low alkalinity 10 mg Zn/L of solution at pH 6 that declines to 6.5 at pH 7, 0.65 at pH 8, and 0.01 mg/L at pH 9 (Spear 1981). Dissolved zinc rarely exceeds 40 pg/L in Canadian rivers and lakes higher concentrations are usually associated with zinc-enriched ore deposits and anthropogenic activities. Marine... 

G. S. Baldwin, S. G. Waley, E. P. Abraham, Identification of Histidine Residues That Act as Zinc Ligands in beta-Lactamase II by Differential Tritium Exchange , Biochem. J. 1979, 179, 459 - 463. 

In Cu,Zn-SOD the copper atom is bound to three histidine groups and the zinc is bound to two histidines and an aspartate oxygen atom (Tainer et al., 1982, 1983) (Fig. 34). The Cu"-Zn distance is 6.3 A. The zinc-ligand geometry is tetrahedral, with a strong distortion toward a trigonal pyramid with aspartic acid at the apex. The coordination of the Cu(II) is tetrahedrally distorted square planar. The axial position of copper is more open on the solvent side than on the protein side probably, water is bound there. The Zn(II) is buried, while the Cu(II) site is solvent accessi-... 

Vallee, B. L., and Auld, D. S. (1990a). Active-site zinc ligands and activated H2O of zinc enzymes. Proc. Natl. Acad. Sci. U.S.A. 87, 220-224. 

B. Hydrogen Bond Networks Involving Zinc Ligands.307... 

Kinetic and Thermodynamic Data for Zinc—Ligand Association" ki... 

Zinc may function to promote the nucleophilicity of a bound solvent molecule in both small-molecule and protein systems. The p/Ca of metal-free H2O is 15.7, and the p/Ca of hexaaquo-zinc, Zn (OH2)6. is about 10 (Woolley, 1975) (Table III). In a novel small-molecule complex the coordination of H2O to a four-coordinate zinc ion reduces the to about 7 (Groves and Olson, 1985) (Fig. 2). This example is particularly noteworthy since it has a zinc-bound solvent molecule sterically constrained to attack a nearby amide carbonyl group as such, it provides a model for the carboxypeptidase A mechanism (see Section IV,B). To be sure, the zinc ligands play an important role in modulating the chemical function of the metal ion in biological systems and their mimics. 

Fig. 11. The slowly hydrolyzed substrate glycyl-L-tyrosine binds to carboxypeptidase A in a nonproductive complex where the amino-terminal glycine complexes the active-site ion (large sphere) to form a five-membered chelate, as in Fig. 10. Protein-bound zinc ligands Glu-72, His-69, and His-196 complete the coordinadon polyhedron of pentacoordinate zinc. Active-site residues are indicated by one-letter abbreviadons and sequence numbers E, glutamate H, hisddine R, arginine Y, tyrosine. [Reprinted with permission from Christianson, D. W., Lipscomb, W. N. (1986) Proc. Natl. Acad. Sci. U.S.A. 83,7568-7572.]...

Hydrogen bond interactions are important for the function of histidine as a zinc ligand. For example, in a survey of zinc-binding motifs, Christianson and Alexander (1989, 1990) reported that head-on and... 

Fig. 13. The Ne-H tautomer of histidine is favored for the free amino acid, but within a protein structure either tautomer may be preferentially stabilized due to hydrogen bond arrangements and other environmental factors. For example, the NS-H tautomer is a frequently observed zinc ligand (Chakrabarti, 1990c).

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