Toward an integrated model of protein-DNA recognition as inferred from NMR studies on the Lac repressor system

Abstract

Sequence-specific protein-DNA interactions are responsible for the regulation of key biological functions such as replication of the genome, initiation of transcription, and repair of damaged DNA. All of these regulatory pathways are built on the foundation that proteins are able to bind selectively to a particular DNA site in the genome. The most challenging issue for specific protein-DNA recognition is that the target sequence is immersed in a huge molar excess of nonspecific DNA sequences, which also compete for the same protein. The distribution of protein between regulatory and nonspecific sequences determines the occupancy of the target site in the cell and, hence, the transcriptional activity of the corresponding promoter. The problem is much more acute than it is for other protein-ligand interactions, because obviously the protein cannot differentiate between these sites on the basis of their size or shape.1 For repressor molecules, such as the lactose (lac) repressor, the problem of finding the correct site is even more severe, as only a few copies ( 10) of the protein exist in the cell. Thus, to compete with the large excess of nonspecific genomic DNA, these proteins have evolved to bind with a very high specificity ratio ( 107).