The research plan is to define and develop the coordination chemistry of zinc, cadmium and mercury as a basis for understanding the biochemistry of proteins that contain these metals. Zinc, cadmium, and mercury-containing metal-cysteine proteins are involved in important biological processes in organisms ranging from viruses to mammals. In 1985, it was recognized that the zinc binding domains in Transcription Factor IIIA provide the structural motif responsible for the interaction of TFIIIA with DNA. In the last four years, there has been an explosion in the number of reports of cysteine-rich metal binding domains in proteins including many of which bind to DNA. Zinc-finger domains have rapidly become on of the major classes of nucleic acid binding proteins. The control of gene expression by protein-DNA interactions is one of the fundamental problems in biology. Included among the zing-finger proteins and related proteins with cysteine- rich metal binding domains are: the HIV-1 enhancer binding protein; the testes determining factor which is thought to be responsible for mammalian sex determination; the steroid hormone receptors; the tat protein from the human immunodeficiency (AIDS) virus which is a powerful trans-activator of HIV-1 gene expression and is essential for virus replication. Other proteins with Zn-cysteine coordination include alcohol dehydrogenase, beta- lactamase II, 5-Aminolevulinate dehydrase, and E. coli RNA Polymerase and metallothionein. Certain bacteria are capable of detoxifying alkylmercurials and inorganic mercury salt via a series of proteins all of which involve Hg-cysteine coordination. The transcription of these proteins is under the control of MerR, which is one of the first members of the new class of metalloregulatory proteins. Also certain yeast cells respond to toxic levels of Cd(II) by producing novel cadmium-sulfide crystallites. The investigations will involve the synthesis, structural characterization and spectroscopic study of complexes of zinc, cadmium and mercury, as well as related metals which have been used as spectroscopic probes for these group IIB metals. Through a systematic study, the coordination chemistry of these metals with biologically relevant ligands will be defined. Structural and spectroscopic parameters will be discovered and developed with the prospect that these parameters can be sued to identify and distinguish differences in coordination number, coordination geometries and the nature and number of ligands bound to a metal-center. The information obtained from these studies will enable the definitive characterization of metal-cysteine centers in proteins. The ultimate goal of this research is to understand how zinc, cadmium and mercury function in biological systems.
