Factors Governing the Different Functions of Zn²⁺-Sites with Identical Ligands in Proteins

In Zn-proteins, structural Zn-sites are mostly Cys-rich lined by two or more Cys residues, whereas catalytic Zn-sites usually contain His or Asp/Glu residues and a water molecule. Here, we reveal many examples outside this trend with Zn²⁺ bound to ligands commonly found in both structural and catalytic Zn-sites, namely, Zn-CC(C/H)x (x = D, E, or H₂O) sites. We show that these atypical Zn-sites are found in all known life forms (i.e., eukaryotes, bacteria, archaea, and viruses) and can serve structural roles in some proteins but catalytic roles in others. By calculating the physical properties of these atypical Zn-binding sites, we elucidate why Zn-CC(C/H)x sites of the same composition can serve structural and catalytic roles in proteins. Furthermore, we found new sequence/structural motifs characteristic of catalytic Zn-CCHw sites and provide guidelines to predict the structural/catalytic role of atypical Zn-CC(C/H)x sites of unknown function. We discuss how our results could help to design inhibitors targeting catalytic Zn-CC(C/H) H₂O sites.