THE CRYSTAL STRUCTURE OF THE HUMAN PAPILLOMAVIRUS 31 E2 DNA BINDING DOMAIN IN THE ABSENCE OF DNA. V. L. Giranda, X. Kong, D. Egan, F. Lindh, T. Holzman, H. S. Yoon, and T. Robins, Abbott Laboratories, Abbott Park, IL 60064

Human papillomaviruses (HPVs) are a causative agent for proliferative epithelial lesions (e.g., warts). Certain HPV serotypes have been causally linked to the development of cervical carcinoma. The papillomavirus E2 gene product is a trans-acting transcriptional regulator. E2 is required for viral replication and is comprised of a DNA binding and activation domains. Previously only the structure of the bovine papillomavirus (BPV) E2 DNA binding domain bound to DNA has been reported.

The crystal structure of the HPV type 31 E2 DNA binding domain has been solved to 2.5 Å resolution in the absence of DNA. The structure is similar to the BPV E2 DNA binding domain. The monomer is comprised of four beta strands which form a beta sheet as well as two alpha helices. The first helix is the DNA recognition helix. The HPV structure, like that of BPV, shows that the DNA binding domains form a tightly associated dimer, with a four stranded beta sheet from each monomer contributing to an eight stranded beta sandwich at the dimer core. The remaining two helices (per monomer) reside on the outside of the dimer. The DNA recognition helices in the absence of DNA are similar to the those seen in the presence of DNA.

The loop between the second and third beta strand is disordered in the HPV structure (no DNA). In the BPV structure this loop is not disordered and associates with the DNA sugar phosphate backbone. Buried at the center of the eight stranded beta sandwich are four hydrophilic residues, two from each monomer, that coordinate a water or solvent ion. This differs significantly from the BPV where the core is occupied exclusively by hydrophobic residues.

This structure will provide a platform on which to base future structure aided drug design. The aim of this design is to create compounds that will inhibit the replication of HPV.