CLASSIFICATION OF MONONUCLEAR ZINC METAL SITES IN PROTEIN STRUCTURES

Our study of the extended metal environment, particularly of the secon d shell, focuses in this paper on zinc sites. Key findings include: (i ) The second shell of mononuclear zinc centers is generally more polar than hydrophobic and prominently features charged residues engaged in an abundance of hydrogen bonding with histidine ligands. Histidine-ac idic or histidine-tyrosine clusters commonly overlap the environment o f zinc ions. (ii) Histidine tautomeric metal bonding patterns in ligat ing zinc ions are mixed. For example, carboxypeptidase A, thermolysin, and sonic hedgehog possess the same ligand group (two histidines, one unibidentate acidic ligand, and a bound water), but their histidine t automeric geometries markedly differ such that the carboxypeptidase A makes only N-delta 1 contacts, thermolysin makes only N-epsilon 2 cont acts, and sonic hedgehog uses one of each. Thus the presence of a simi lar ligand cohort does not necessarily imply the same topology or func tion at the active site. (iii) Two close histidine ligands HXmH, m les s than or equal to 5, rarely both coordinate a single metal ion in the N-delta 1 tautomeric conformation, presumably to avoid steric conflic ts. Mononuclear zinc sites can be classified into six types depending on the ligand composition and geometry. Implications of the results ar e discussed in terms of divergent and convergent evolution.