STRUCTURE OF THE LACTOSE OPERON REPRESSOR AND ITS COMPLEXES WITH DNA AND INDUCER. M. A. Kercher^*, G. Chang⁺, N. C. Horton^*, P. Lu^*, J. H. Miller^{[[daggerdbl]]}, H. C. Pace^*, M. Lewis⁺, ⁺Department of Biochemistry and Biophysics and ^*Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA and ^{[[daggerdbl]]}Department of Microbiology and Molecular Genetics, University of California, Los Angeles, CA 90024, USA

In 1961 Jacob and Monod proposed a model for gene regulation which was widely adopted as a paradigm. The model was based on a "repressor" molecule that had not at that time been isolated but later became known as lac repressor. Determination of the 3-dimensional structures of three different forms of the lac repressor protein (the intact lac repressor, the lac repressor bound to the gratuitous inducer isopropyl-1-[[beta]]-D-thiogalactoside (IPTG) and the lac repressor complexed with two 21 base-pair symmetric operator DNA duplex deoxyoligonucleotides) makes the analysis of the mechanism of gene regulation possible. Comparison of the induced and repressed forms of the protein at the dimer level show that a conformational change in the core of the structure results in changes in the distant DNA-binding areas of the protein. Examination of the protein at the tetramer level leads to a model of a 93 base-pair repression loop corresponding to the lac operon -82 to +11 region in which lac repressor acts with the catabolite activating protein is presented. A correlation of the site-specific mutational analysis with the 3-dimensional structures is also presented.(supported by NIH and US ARO)