Restriction of S-adenosylmethionine conformational freedom by knotted protein binding sites
| Autor: | Adam Stasiulewicz, Ewa K. Nawrocka, Krzysztof Kazimierczuk, Piotr Setny, Agata P. Perlinska, Joanna I. Sulkowska |
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| Rok vydání: | 2020 |
| Předmět: |
Proteomics
0301 basic medicine Protein Folding S-Adenosylmethionine Magnetic Resonance Spectroscopy Methyltransferase Ribose Amino Acid Motifs Protein Data Bank (RCSB PDB) Plasma protein binding Biochemistry Database and Informatics Methods Protein Structure Databases chemistry.chemical_compound Molecular dynamics Methionine 0302 clinical medicine Protein structure Biochemical Simulations Macromolecular Structure Analysis Biology (General) Amino Acids Databases Protein chemistry.chemical_classification Principal Component Analysis tRNA Methyltransferases Ecology Organic Compounds Nucleotides Proteomic Databases Chemistry Monosaccharides Temperature Enzymes Computational Theory and Mathematics Modeling and Simulation Physical Sciences Protein Binding Research Article Protein Structure QH301-705.5 Stereochemistry Glycine Carbohydrates Drug design Molecular Dynamics Simulation Research and Analysis Methods DNA-binding protein 03 medical and health sciences Cellular and Molecular Neuroscience Protein Domains Genetics Sulfur Containing Amino Acids Molecule Computer Simulation Binding site Molecular Biology Ecology Evolution Behavior and Systematics Binding Sites Adenine Organic Chemistry Chemical Compounds Computational Biology Water Biology and Life Sciences Proteins Methionine Adenosyltransferase Methyltransferases Biological Databases 030104 developmental biology Enzyme Solvents Enzymology 030217 neurology & neurosurgery |
| Zdroj: | PLoS Computational Biology PLoS Computational Biology, Vol 16, Iss 5, p e1007904 (2020) |
| ISSN: | 1553-7358 |
| Popis: | S-adenosylmethionine (SAM) is one of the most important enzyme substrates. It is vital for the function of various proteins, including large group of methyltransferases (MTs). Intriguingly, some bacterial and eukaryotic MTs, while catalysing the same reaction, possess significantly different topologies, with the former being a knotted one. Here, we conducted a comprehensive analysis of SAM conformational space and factors that affect its vastness. We investigated SAM in two forms: free in water (via NMR studies and explicit solvent simulations) and bound to proteins (based on all data available in the PDB and on all-atom molecular dynamics simulations in water). We identified structural descriptors—angles which show the major differences in SAM conformation between unknotted and knotted methyltransferases. Moreover, we report that this is caused mainly by a characteristic for knotted MTs compact binding site formed by the knot and the presence of adenine-binding loop. Additionally, we elucidate conformational restrictions imposed on SAM molecules by other protein groups in comparison to conformational space in water. Author summary The topology of a folded polypeptide chain has great impact on the resulting protein function and its interaction with ligands. Interestingly, topological constraints appear to affect binding of one of the most ubiquitous substrates in the cell, S-adenosylmethionine (SAM), to its target proteins. Here, we demonstrate how binding sites of specific proteins restrict SAM conformational freedom in comparison to its unbound state, with a special interest in proteins with non-trivial topology, including an exciting group of knotted methyltransferases. Using a vast array of computational methods combined with NMR experiments, we identify key structural features of knotted methyltransferases that impose unorthodox SAM conformations. We compare them with the characteristics of standard, unknotted SAM binding proteins. These results are significant for understanding differences between analogous, yet topologically different enzymes, as well as for future rational drug design. |
| Databáze: | OpenAIRE |
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