3mi7 | pdb_00003mi7
An Enhanced Repressor of Human Papillomavirus E2 Protein
Structural highlights
Function[VE2_HPV16] Plays an accessory role in initiation of DNA replication. A dimer of E2 interacts with a dimer of E1 in order to improve specificity of E1 DNA binding activity. Once the complex recognizes and binds DNA at specific sites, the E2 dimer is removed from DNA. E2 also regulates viral transcription through binding to the E2RE response element (5'-ACCNNNNNNGGT-3') present in multiple copies in the regulatory regions of the viral genome. Activates or represses transcription depending on E2RE's position with regards to proximal promoter elements including the TATA-box. Repression occurs by sterically hindering the assembly of the transcription initiation complex.[1] [2] [3] Publication Abstract from PubMedPapillomaviruses are causative agents of cervical and anogenital cancers. The viral E2 protein mediates viral DNA replication and transactivation of viral oncogenes and thus represents a specific target for therapeutic intervention. Short forms of E2, E2R, contain only the C-terminal dimerization domain, and repress the normal function of E2 due to formation of an inactive heterodimer. Using structure-guided design, we replaced conserved residues at the dimer interface to design a heterodimer with increased stability. One E2R mutant in which histidine was replaced by a glutamate residue showed preferential heterodimer formation in vitro, as well as an increase in plasticity at the interface, as a result of histidine-glutamate pair formation, as observed spectroscopically and in the crystal structure, determined to 2.2-A resolution. In addition, the enhanced E2R showed greater repression of transcription from E2-responsive reporter plasmids in mammalian cell culture. Recent advances in protein delivery into the cell raise the possibility of using exogenously added proteins as therapeutic agents. More generally, this approach may be used to target the subunit interfaces of any multisubunit protein having a similar mechanism of action.-Bose, K., Meinke, G., Bohm, A., Baleja, J. D. Design and characterization of an enhanced repressor of human papillomavirus E2 protein. Design and characterization of an enhanced repressor of human papillomavirus E2 protein.,Bose K, Meinke G, Bohm A, Baleja JD FASEB J. 2011 Jul;25(7):2354-61. Epub 2011 Apr 11. PMID:21482558[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
