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J. Biol. Chem., Vol. 281, Issue 1, 578-586, January 6, 2006

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Structure of the Human Papillomavirus E7 Oncoprotein and Its Mechanism for Inactivation of the Retinoblastoma Tumor Suppressor^*

Xin Liu, Adrienne Clements¶, Kehao Zhao, and Ronen Marmorstein¶1

From the The Wistar Institute, The Department of Chemistry, University of Pennsylvania, and ^¶The Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

The E7 oncoprotein from human Papillomavirus (HPV) mediates cell transformation in part by binding to the human pRb tumor suppressor protein and E2F transcription factors, resulting in the dissociation of pRb from E2F transcription factors and the premature cell progression into the S-phase of the cell cycle. This activity is mediated by the LXCXE motif and the CR3 zinc binding domain of the E7 protein. In this study we report the x-ray crystal structure of the CR3 region of HPV E7 and a structure-based mutational analysis to investigate its mode of pRb and E2F binding and E2F displacement from pRb. The structure reveals a novel zinc-bound E7-CR3 obligate homodimer that contains two surface patches of sequence conservation. Mutation of residues within these patches reveals that one patch is required for pRb binding, whereas the other is required for E2F binding. We also show that both E7-mediated interactions are required to disrupt pRb·E2F complexes. Based on these studies we present a mechanistic model for how E7 displaces E2F from pRb. Because the CR3 region of HPV E7 has no detectable homology to other human proteins, the structure-function studies presented here provide an avenue for developing small molecule compounds that inhibit HPV-E7-mediated cell transformation.

Received for publication, August 2, 2005 , and in revised form, October 5, 2005.

The atomic coordinates and structure factors (code 2B9D (HPV 1AE7-(44–93))) 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 National Institutes of Health grants (to R. M.) and by a grant from the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health awarded to the Wistar Institute. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental material.

¹ To whom correspondence should be addressed: The Wistar Institute, 3601 Spruce St., Rm. 327, Philadelphia, PA 19104. Tel.: 215-898-5006; Fax: 215-898-0381; E-mail: marmor{at}wistar.upenn.edu.

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