Conformational flexibility influences structure–function relationships in nucleic acid N-methyl demethylases
| Autor: | Tatyana G. Karabencheva-Christova, Jon Ainsley, Martin Evison, Sodiq O. Waheed, Shobhit S. Chaturvedi, Christopher J. Schofield, Rajeev Ramanan, Jennifer M. Ames, Christo Z. Christov |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Oxygenase Stereochemistry Protein Conformation AlkB Alpha-Ketoglutarate-Dependent Dioxygenase FTO DNA Single-Stranded Molecular Dynamics Simulation 010402 general chemistry Crystallography X-Ray 01 natural sciences Biochemistry Substrate Specificity 03 medical and health sciences chemistry.chemical_compound Catalytic Domain Humans Physical and Theoretical Chemistry biology Escherichia coli K12 Adenine Escherichia coli Proteins Organic Chemistry Structure function AlkB Enzymes Active site RNA SUPERFAMILY DNA Methylation 0104 chemical sciences 030104 developmental biology chemistry biology.protein Nucleic acid DNA Protein Binding |
| DOI: | 10.1039/c9ob00162j |
| Popis: | N-Methylation of DNA/RNA bases can be regulatory or damaging and is linked to diseases including cancer and genetic disorders. Bacterial AlkB and human FTO are DNA/RNA demethylases belonging to the Fe(II) and 2-oxoglutarate oxygenase superfamily. Modelling studies reveal conformational dynamics influence structure–function relationships of AlkB and FTO, e.g. why 1-methyladenine is a better substrate for AlkB than 6-methyladenine. Simulations show that the flexibility of the double stranded DNA substrate in AlkB influences correlated motions, including between the core jelly-roll fold and an active site loop involved in substrate binding. The FTO N- and C-terminal domains move in respect to one another in a manner likely important for substrate binding. Substitutions, including clinically observed ones, influencing catalysis contribute to the network of correlated motions in AlkB and FTO. Overall, the calculations highlight the importance of the overall protein environment and its flexibility to the geometry of the reactant complexes. |
| Databáze: | OpenAIRE |
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