1. Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 37th and Hamilton Walk, Philadelphia, Pennsylvania 19102-6059, USA
2. Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA
3. Present address: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.

Correspondence to: Mitchell Lewis¹ Correspondence and requests for materials should be addressed to M.L. (Email: lewis@mail.med.upenn.edu).

Bacteriophage has for many years been a model system for understanding mechanisms of gene regulation¹. A 'genetic switch' enables the phage to transition from lysogenic growth to lytic development when triggered by specific environmental conditions. The key component of the switch is the cI repressor, which binds to two sets of three operator sites on the chromosome that are separated by about 2,400 base pairs (bp)^{2, 3}. A hallmark of the system is the pairwise cooperativity of repressor binding⁴. In the absence of detailed structural information, it has been difficult to understand fully how repressor molecules establish the cooperativity complex. Here we present the X-ray crystal structure of the intact cI repressor dimer bound to a DNA operator site. The structure of the repressor, determined by multiple isomorphous replacement methods, reveals an unusual overall architecture that allows it to adopt a conformation that appears to facilitate pairwise cooperative binding to adjacent operator sites.