A new activity of anti-HIV and anti-tumor protein GAP31: DNA adenosine glycosidase – Structural and modeling insight into its functions
| Autor: | Xiang-Peng Kong, Paul L. Huang, Yongtao Sun, John Z. H. Zhang, Dawei Zhang, Hao Chia Chen, Sylvia Lee-Huang, Huiguang Li, Philip Lin Huang |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Protein Conformation Virus Integration Biophysics Guanosine Antineoplastic Agents Biology Crystallography X-Ray Biochemistry DNA Glycosylases Structure-Activity Relationship chemistry.chemical_compound Sticky and blunt ends Catalytic Domain medicine Humans HIV Integrase Inhibitors Molecular Biology HIV Long Terminal Repeat chemistry.chemical_classification DNA ligase Base Sequence Oligonucleotide Adenine RNA Cell Biology Adenosine Oligodeoxyribonucleotides chemistry Plant protein DNA Viral Ribosome Inactivating Proteins Type 1 DNA medicine.drug |
| Zdroj: | Biochemical and Biophysical Research Communications. 391:340-345 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2009.11.060 |
| Popis: | We report here the high-resolution atomic structures of GAP31 crystallized in the presence of HIV-LTR DNA oligonucleotides systematically designed to examine the adenosine glycosidase activity of this anti-HIV and anti-tumor plant protein. Structural analysis and molecular modeling lead to several novel findings. First, adenine is bound at the active site in the crystal structures of GAP31 to HIV-LTR duplex DNA with 5' overhanging adenosine ends, such as the 3'-processed HIV-LTR DNA but not to DNA duplex with blunt ends. Second, the active site pocket of GAP31 is ideally suited to accommodate the 5' overhanging adenosine of the 3'-processed HIV-LTR DNA and the active site residues are positioned to perform the adenosine glycosidase activity. Third, GAP31 also removes the 5'-end adenine from single-stranded HIV-LTR DNA oligonucleotide as well as any exposed adenosine, including that of single nucleotide dAMP but not from AMP. Fourth, GAP31 does not de-purinate guanosine from di-nucleotide GT. These results suggest that GAP31 has DNA adenosine glycosidase activity against accessible adenosine. This activity is distinct from the generally known RNA N-glycosidase activity toward the 28S rRNA. It may be an alternative function that contributes to the antiviral and anti-tumor activities of GAP31. These results provide molecular insights consistent with the anti-HIV mechanisms of GAP31 in its inhibition on the integration of viral DNA into the host genome by HIV-integrase as well as irreversible topological relaxation of the supercoiled viral DNA. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect