Reactivity of zinc finger cores: Analysis of protein packing and electrostatic screening

The chemical stability of 207 zinc fingers, derived from 92 experimental pr otein structures, is evaluated according to the protein packing and electro static screening of their zinc cores. These properties are used as measures of the protein protection of zinc cores, to predictively rank relative zin c finger reactivities and assess differences in function. On average, there is a substantial and concomitant increase in the screening of increasingly anionic core motifs, suggesting zinc fingers have evolved in a manner that promotes shielding of their potentially reactive core thiolates. In contra st, enzymatic zinc cores are functionally differentiated by negative electr ostatic screening. Zinc finger cores are predominantly screened by networks of backbone:core NW-S hydrogen bonds that electronically stabilize core th iolates and enhance backbone packing. Stabilizing protein:core interactions can be mapped to conserved residues, including [Arg,Lys]:core salt-bridges in some protein families. Labile zinc fingers are identified by poorly scr eened cores, possibly indicating redox or metallothionein (MT) regulated fu nction. Consistent with experiment, the cores of the C-terminal finger of t he human immunodeficiency virus type I (HIV-I) nucleocapsid protein p7 (NCp 7) and Escherichia coli Ada protein (Ada) "finger" are identified as reacti ve. The C-terminal zinc fingers of nuclear receptors are predicted to be th e most labile in this study, particularly the human estrogen receptor (hER) , which contains a triad of reactive thiolates. We propose that hER DNA bin ding is redox and MT regulated through the C-terminal finger and that,weak electrophilic agents may inhibit hER-mediated transcription, implicated in breast cancer progression.