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J. Biol. Chem., Vol. 278, Issue 25, 23094-23100, June 20, 2003

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X-ray Crystal Structure of an IB·NF-B p65 Homodimer Complex^*

Shiva Malek   ¶, De-Bin Huang  , Tom Huxford , Sankar Ghosh || and Gourisankar Ghosh  **

From the Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California 92093-0359 and ^||Section of Immunobiology and Department of Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520

We report the crystal structure of a murine IB·NF-B p65 homodimer complex. Crystallographic models were determined for two triclinic crystalline systems and refined against data at 2.5 and 2.1 Å. The overall complex structure is similar to that of the IB·NF-B p50/p65 heterodimer complex. One NF-B p65 subunit nuclear localization signal clearly contacts IB, whereas a homologous segment from the second subunit of the homodimer is mostly solvent-exposed. The unique 47-amino acid insertion between ankyrin repeats three and four of IB is mostly disordered in the structure. Primary sequence analysis and differences in the mode of binding at the IB sixth ankyrin repeat and NF-B p65 homodimer suggest a model for nuclear IB·NF-B·DNA ternary complex formation. These unique structural features of IB may contribute to its ability to mediate persistent NF-B activation.

Received for publication, January 30, 2003 , and in revised form, April 4, 2003.

The atomic coordinates and structure factors (code 1K3Z and 1OY3) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by United States Public Health Service Grant CA-78749 from the National Cancer Institute and an Alfred P. Sloan foundation fellowship (to G. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^¶ Present address: Aurora Biosciences Corp., 11010 Torreyana Rd., San Diego, CA 92121.

^** To whom correspondence should be addressed: Dept. of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, MC 0359, La Jolla, CA 92093-0359. Tel.: 858-822-0469; Fax: 858-534-7042; E-mail: gghosh{at}chem.ucsd.edu.

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