MODEL OF LACTOSE REPRESSOR CORE BASED ON ALIGNMENT WITH SUGAR-BINDINGPROTEINS IS CONCORDANT WITH GENETIC AND CHEMICAL-DATA

Using primary sequence similarity to arabinose-binding protein, D-gluc ose/D-galactose-binding protein, and ribose-binding protein (Vyas, N. K., Vyas, M. N., and Quiocho, F. A. (1991) J. Biol. Chem. 266, 5226-52 37; Mowbray, S. L., and Cole, L. B. (1992) J. Mol. Biol. 225, 155-175) , the core domain (residues 62-323) of the bacterial regulatory protei n lac repressor has been aligned to these sugar-binding proteins of kn own structure. Although the sequence identity is not striking, there i s strong overall homology based on two separate matrix scoring systems (minimum base change per codon (MBC/C) and amino acid homology per re sidue (AAH/R)) (mean score: MBC/C < 1.25, AAH/R > 5.50; random sequenc es: MBC/C = 1.45, AAH/R = 4.46). Similarly, the predicted secondary st ructure of the repressor exhibits excellent agreement with the known s econdary structures of the sugar-binding proteins. Using this primary sequence alignment, the tertiary structure of the core domain of the l ac repressor has been modeled based on the known structures of the sug ar-binding proteins as templates. While the structure deduced for the repressor is hypothetical, the model generated allows a comparison bet ween the predicted tertiary arrangement and the wealth of genetic and chemical data elucidated for the repressor. Important residues involve d in operator and sugar binding and in protein assembly have been iden tified using genetic methods, and placement of these residues in the m odel is consistent with their known function. This approach, therefore , provides a means to visualize the core domain of the lac repressor t hat allows interpretation of genetic and chemical data for specific re sidues and rational design of future experiments.