Plasticity in protein–DNA recognition: lac repressor interacts with its natural operator O1 through alternative conformations of its DNA-binding domain

The lac repressor-operator system is a model system for understanding protein-DNA interactions and allosteric mechanisms in gene regulation. Despite the wealth of biochemical data provided by extensive mutations of both repressor and operator, the speci®c recognition mechanism of the natural lac operators by lac repressor has remained elusive. Here we present the ®rst high-resolution structure of a dimer of the DNA-binding domain of lac repressor bound to its natural operator O1. The global positioning of the dimer on the operator is dramatically asymmetric, which results in a different pattern of speci®c contacts between the two sites. Speci®c recognition is accomplished by a combination of elongation and twist by 48° of the right lac subunit relative to the left one, signi®cant rearrangement of many side chains as well as sequence-dependent deformability of the DNA. The set of recognition mechanisms involved in the lac repressor±operator system is unique among other protein-DNA complexes and presents a nice example of the adaptability that both proteins and DNA exhibit in the context of their mutual interaction.