Structural and Functional Aspects of Metal Sites in Biology.

The field of bioinorganic chemistry is at a propitious stage of development. Ever more complex metallobiomolecules are isolated and purified, physical methodologies and attendant theories probe even more deeply into the intricacies of electronic structure and structural dynamics, chemical syntheses of protein and metal coordination units become more sophisticated, and biochemical syntheses with sitedirected mutagenesis disclose functions of specific amino acid residues. Inasmuch as explication of function is the ultimate investigative goal of any biological process, and function is inseparable from geometric structure, the ever-increasing crystallographic database of protein structure assumes an even greater significance. One need only contemplate the active-site structures of, inter alia, such complex molecules as nitrogenase,1 cytochrome c oxidase,2,3 sulfite reductase,4 and ceruloplasmin5 reported within the last four years, to recognize that these can now be conceived at a molecular level of detail. For present purposes, a protein-bound metal site consists of one or more metal ions and all protein side chain and exogenous bridging and terminal ligands that define the first coordination sphere of each metal ion. Such sites can be classified into five basic types with the indicated functions: (i) structuralsconfiguration (in part) of protein tertiary and/or quaternary structure; (ii) storagesuptake, binding, and release of metals in soluble form; (iii) electron transfersuptake, release, and storage of electrons; (iv) dioxygen bindingsmetal-O2 coordination and decoordination; (v) catalyticssubstrate binding, activation, and turnover. We present here a classification and structure/ function analysis of native metal sites based on these functions, where v is an extensive class subdivided by the type of reaction catalyzed (dismutases, oxidases and oxygenase, nitrogenases and hydrogenases, oxotransferases, hydrolases, and others). In order to restrict the scope of information presented to a manageable size, sites containing heme and corrin units have been excluded with only several exceptions. Here, structure refers primarily to crystallographic information. Not included in the tabulations of site structures which follow are (partial) structural deductions from X-ray absorption spectroscopy, NMR, and other spectroscopic techniques. Within this purview, coverage of the various site types is extensive, but not exhaustive. The purpose of this exposition is to present examples of all types of sites and to relate, insofar as is currently feasible, the structure and function of selected types. Functional aspects of the latter and other sites are the subjects of accompanying contributions in this issue. We largely confine our considerations to the sites themselves, with due recognition that these site features are coupled to protein structure at all levels. In the next section, the coordination chemistry of metalloprotein sites and the unique properties of a protein as a ligand are briefly summarized. In section III, structure/function relationships are systematically explored and tabulations of structurally defined sites presented. Other compilations of metalloprotein structures have been made earlier.6 Finally, in section IV, future directions in bioinorganic research in the context of metal site chemistry are considered. Throughout, it will be evident that a high-resolution metalloprotein structure provides the initial point for penetrating the complexities of site function. But as such, it is only the beginning, and not the end, of any inquiry into function.