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J. Biol. Chem., Vol. 279, Issue 8, 6976-6985, February 20, 2004

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Crystal Structure of the E2 Transactivation Domain of Human Papillomavirus Type 11 Bound to a Protein Interaction Inhibitor^*

Yong Wang, René Coulombe, Dale R. Cameron¶, Louise Thauvette, Marie-Josée Massariol, Lynn M. Amon¶, Dominique Fink, Steve Titolo, Ewald Welchner, Christiane Yoakim¶, Jacques Archambault, and Peter W. White||

From the Department of Biological Sciences and ^¶Department of Chemistry, Boehringer Ingelheim (Canada) Ltd., Laval, Quebec H7S 2G5, Canada and the Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 06877

Interaction between the E2 protein and E1 helicase of human papillomaviruses (HPVs) is essential for the initiation of viral DNA replication. We recently described a series of small molecules that bind to the N-terminal transactivation domain (TAD) of HPV type 11 E2 and inhibits its interaction with E1 in vitro and in cellular assays. Here we report the crystal structures of both the HPV11 TAD and of a complex between this domain and an inhibitor, at 2.5- and 2.4-Å resolution, respectively. The HPV11 TAD structure is very similar to that of the analogous domain of HPV16. Inhibitor binding caused no significant alteration of the protein backbone, but movements of several amino acid side chains at the binding site, in particular those of Tyr-19, His-32, Leu-94, and Glu-100, resulted in the formation of a deep hydrophobic pocket that accommodates the indandione moiety of the inhibitor. Mutational analysis provides functional evidence for specific interactions between Tyr-19 and E1 and between His-32 and the inhibitor. A second inhibitor molecule is also present at the binding pocket. Although evidence is presented that this second molecule makes only weak interactions with the protein and is likely an artifact of crystallization, its presence defines additional regions of the binding pocket that could be exploited to design more potent inhibitors.

Received for publication, October 16, 2003 , and in revised form, November 21, 2003.

The atomic coordinates and structure factors (code 1R6K and 1R6N) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* 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.

^|| To whom correspondence should be addressed: Dept. of Biological Sciences, Boehringer Ingelheim (Canada) Ltd., 2100 Cunard St., Laval, Quebec H7S 2G5, Canada. Tel.: 450-682-4640 (ext. 4269); Fax: 450-682-4642; E-mail: pwhite{at}lav.boehringer-ingelheim.com.

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