METAL IONS IN PROTEINS

Jenny P. Glusker, Amy K. Katz, H. L. Carrell, Liat Shimoni-Livny, Carol E. Afshar, Trixie Wagner, and Charles W. Bock.

The Institute for Cancer Research, The Fox Chase Cancer Center, Philadelphia, PA 19111 USA.

Metal ions are preferentially bound by negatively charged side chains of proteins, that is, aspartate and glutamate side chains. Further binding of certain metal ions can be found with functional oxygen groups such as main-chain carbonyl groups and the hydroxyl groups of serine, threonine and tyrosine side chains, nitrogen in main-chain -NH- groups and histidine side chains and sulfur in thiol groups in cysteine side chains. We have examined the relative tendency for selected metal ions to bind to oxygen, nitrogen and sulfur atoms in ligands in crystal structures in the Cambridge Crystallographic Database and have then studied their roles in proteins, particularly the active sites of enzymes.

We describe the preferred binding of magnesium, calcium, manganese, zinc, and lead in small molecules and proteins, with attention to metal-binding motifs found in the proteins. The findings have been augmented by the results of ab initio molecular orbital studies in which we have examined the energy penalty for moving water molecules between the inner and next coordination spheres of a given metal ion. For magnesium it is found that by far the preferred coordination number is six, to oxygen atoms in ligands. Zinc ions, which have a similar size, can have coordination numbers of four, five or six with almost no energy penalty for changing between these three numbers and the preferred ligands can have sulfur, nitrogen or oxygen atoms binding to the metal ion. A common binding motif of magnesium ions involves a hydrated carboxylate group which binds in a bidentate manner to the metal ion. This motif is less common for zinc and manganese ions in proteins. The effects of the metal ions on the ability of a metal ion-bound water molecule to be deprotonated has also been studied.

Lead has a more complicated stereochemistry in view of the presence of a lone pair of electrons when in the divalent state. The extent to which this is expressed by a void in the binding of ligands will be described complemented by ab initio molecular orbital calculations to follow the disposition of the electrons and a crystal structure of lead-containing D-xylose isomerase.

This work is supported by a grant (CA-10925) from the National Institutes of Health, U.S. Public Health Service.