Reactivity of zinc finger cores: analysis of protein packing and electrostatic screening.
The chemical stability of 207 zinc fingers, derived from 92 experimental protein structures, is evaluated according to the protein packing and electrostatic screening of their zinc cores. These properties are used as measures of the protein protection of zinc cores, to predictively rank relative zinc 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 contrast, enzymatic zinc cores are functionally differentiated by negative electrostatic screening. Zinc finger cores are predominantly screened by networks of backbone:core NH-S hydrogen bonds that electronically stabilize core thiolates 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 screened cores, possibly indicating redox or metallothionein (MT) regulated function. Consistent with experiment, the cores of the C-terminal finger of the human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein p7 (NCp7) and Escherichia coli Ada protein (Ada) "finger" are identified as reactive. The C-terminal zinc fingers of nuclear receptors are predicted to be the most labile in this study, particularly the human estrogen receptor (hER), which contains a triad of reactive thiolates. We propose that hER DNA binding 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.
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Frederick Cancer Research and Development Center, Screening Technologies Branch, DCTD, NCI, NIH, SAIC, Frederick, Maryland 21702, USA. covell@faxpdc.ncifcrf.gov
Covell
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D008958:Models, Molecular; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D055672:Static Electricity; D016335:Zinc Fingers
D011506:Proteins