MOLECULAR MODELING OF THE AMINO-TERMINAL ZINC RING DOMAIN OF BRCA1

The equine herpes virus zinc ring domain nuclear magnetic resonance st ructure was used for homology-based modeling of the amino-terminal zin c ring domain of the BRCA1 breast and ovarian cancer susceptibility ge ne. The zinc ring domain of BRCA1 is of particular interest because it is the location of significant and frequently occurring missense (Cys (61)Gly, Cys(64)Gly, and Cys(64)Tyr) and frameshift (185delAG) mutatio ns observed in several high-risk kindreds. The BRCA1 zinc ring domain possesses 54% sequence similarity with the equine herpes virus zinc ri ng domain. The model structure undergoes little conformational varianc e after 140 ps of solvated molecular dynamics. This model proposes BRC A1 zinc ring domain residues that mag play a role in DNA binding and/o r protein-protein interactions. These predictions provide a point of d eparture for the design of mutants to probe BRCA1 zinc ring domain fun ctionality.