Recognition of DNA interstrand cross-link of antitumor cisplatin by HMGB1 protein
Language English Country United States Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
12564926
DOI
10.1021/bi026695t
Knihovny.cz E-resources
- MeSH
- DNA Adducts chemistry MeSH
- Amino Acid Motifs MeSH
- Amino Acids chemistry MeSH
- Cisplatin chemistry MeSH
- Deoxyribose chemistry MeSH
- Protein Footprinting MeSH
- Nucleic Acid Heteroduplexes chemistry MeSH
- Hydroxyl Radical chemistry MeSH
- Rats MeSH
- Lysine chemistry MeSH
- Models, Molecular MeSH
- Molecular Sequence Data MeSH
- Base Pairing MeSH
- Peptide Fragments chemistry MeSH
- Surface Properties MeSH
- HMGB1 Protein chemistry isolation & purification MeSH
- Antineoplastic Agents chemistry MeSH
- Protons MeSH
- Cross-Linking Reagents chemistry MeSH
- Solvents MeSH
- Amino Acid Sequence MeSH
- Protein Structure, Tertiary MeSH
- Protein Binding MeSH
- Hydrogen Bonding MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- DNA Adducts MeSH
- Amino Acids MeSH
- Cisplatin MeSH
- Deoxyribose MeSH
- Nucleic Acid Heteroduplexes MeSH
- Hydroxyl Radical MeSH
- Lysine MeSH
- Peptide Fragments MeSH
- HMGB1 Protein MeSH
- Antineoplastic Agents MeSH
- Protons MeSH
- Cross-Linking Reagents MeSH
- Solvents MeSH
Several proteins that specifically bind to DNA modified by cisplatin, including those containing HMG-domains, mediate antitumor activity of this drug. Oligodeoxyribonucleotide duplexes containing a single, site-specific interstrand cross-link of cisplatin were probed for recognition by the rat chromosomal protein HMGB1 and its domains A and B using the electrophoretic mobility-shift assay. It has been found that the full-length HMGB1 protein and its domain B to which the lysine-rich region (seven amino acid residues) of the A/B linker is attached at the N-terminus (the domain HMGB1b7) specifically recognize DNA interstrand cross-linked by cisplatin. The affinity of these proteins to the interstrand cross-link of cisplatin is not very different from that to the major 1,2-GG intrastrand cross-link of this drug. In contrast, no recognition of the interstrand cross-link by the domain B lacking this region or by the domain A with or without this lysine-rich region attached to its C-terminus is noticed under conditions when these proteins readily bind to 1,2-GG intrastrand adduct. A structural model for the complex formed between the interstrand cross-linked DNA and the domain HMGB1b7 was constructed and refined using molecular mechanics and molecular dynamics techniques. The calculated accessible areas around the deoxyribose protons correlate well with the experimental hydroxyl radical footprint. The model suggests that the only major adaptation necessary for obtaining excellent surface complementarity is extra DNA unwinding (approximately 40 degrees ) at the site of the cross-link. The model structure is consistent with the hypothesis that the enhancement of binding affinity afforded by the basic lysine-rich A/B linker is a consequence of its tight binding to the sugar-phosphate backbone of both DNA strands.
Biochemistry. 2003 Apr 8;42(13):3996 PubMed
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