Molecular recognition of the nucleosomal “supergroove”

doi:10.1073/pnas.0401743101

Molecular recognition of the nucleosomal “supergroove”

^*Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523-1870; ^†Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125; and ^‡Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037

Contributed by Peter B. Dervan, March 16, 2004

Abstract

Chromatin is the physiological substrate in all processes involving eukaryotic DNA. By organizing 147 base pairs of DNA into two tight superhelical coils, the nucleosome generates an architecture where DNA regions that are 80 base pairs apart on linear DNA are brought into close proximity, resulting in the formation of DNA “supergrooves.” Here, we report the design of a hairpin polyamide dimer that targets one such supergroove. The 2-Å crystal structure of the nucleosome–polyamide complex shows that the bivalent “clamp” effectively crosslinks the two gyres of the DNA superhelix, improves positioning of the DNA on the histone octamer, and stabilizes the nucleosome against dissociation. Our findings identify nucleosomal supergrooves as platforms for molecular recognition of condensed eukaryotic DNA. In vivo, supergrooves may foster synergistic protein–protein interactions by bringing two regulatory elements into juxtaposition. Because supergroove formation is independent of the translational position of the DNA on the histone octamer, accurate nucleosome positioning over regulatory elements is not required for supergroove participation in eukaryotic gene regulation.

Footnotes

↵ § To whom correspondence may be addressed. E-mail: kluger{at}lamar.colostate.edu or dervan{at}caltech.edu.
Abbreviations: NCP, nucleosome core particle; PA, polyamide.
Data deposition: The atomic coordinates and structure factors for NCP146–PW12 have been deposited in the Protein Data Bank, www.pdb.org (PDB ID code 1S32).