Computer simulations reveal changes in the conformational space of the transcriptional regulator MosR upon the formation of a disulphide bond and in the collective motions that regulate its DNA-binding affinity
| Autor: | Eduardo Horjales, Amanda Souza Câmara |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
SIMULAÇÃO Molecular biology Protein Conformation Regulator lcsh:Medicine Molecular Dynamics Biochemistry Dissociation (chemistry) chemistry.chemical_compound Molecular dynamics Computational Chemistry Transcriptional regulation Biochemical Simulations Amino Acids lcsh:Science chemistry.chemical_classification Multidisciplinary Crystallography Chemistry Organic Compounds Physics Condensed Matter Physics Nucleic acids Physical Sciences Crystal Structure Oxidation-Reduction Research Article Protein Binding 030103 biophysics Biophysical Simulations Protein Structure Biophysics Molecular Dynamics Simulation 03 medical and health sciences Motion Bacterial Proteins Oxidoreductase DNA-binding proteins Genetics Solid State Physics Sulfur Containing Amino Acids Cysteine lcsh:R Organic Chemistry Chemical Compounds Biology and Life Sciences Computational Biology DNA structure Proteins DNA-binding domain DNA Mycobacterium tuberculosis Macromolecular structure analysis 030104 developmental biology Helix lcsh:Q Transcription Factors |
| Zdroj: | PLoS ONE Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP PLoS ONE, Vol 13, Iss 2, p e0192826 (2018) |
| ISSN: | 1932-6203 |
| Popis: | M. tuberculosis oxidation sense Regulator (MosR) is a transcriptional regulator from Mycobacterium tuberculosis. It senses the environment oxidation and regulates the expression of a secreted oxidoreductase, thus defending the bacilli against oxidative stress from the phagosome. While most of the members of the Multiple antibiotics resistance Regulator (MarR) family are ligand-responsive, MosR may dissociate from its DNA site upon formation of an intrachain disulphide bond. However, the structure of MosR in its oxidized state is not known, and it is not clear how the formation of this disulphide bond would lead to the conformational changes required for dissociation of the DNA. Nonetheless, MosR presents two crystallographically resolved conformations in its reduced state: bound and unbound to DNA. We managed to simulate MosR unbound to the DNA, both in the presence and in the absence of the disulphide bond. Our results indicate that this disulphide bond precludes the N-terminal residues from adopting a conformation that stands in-between the helix α1 and the DNA binding domain (DBD) from the other chain. Once this conformation is achieved in the reduced state, this DBD detaches from the dimerization domain and becomes more flexible, being able to perform motions with higher amplitude and higher degree of collectivity. Only then, MosR may achieve a conformation where its recognition helices fit into the major grooves of its DNA site. The analysis of the collective motions performed by MosR, during the different situations sampled by the molecular dynamics (MDs), was only possible by the method of filtering harmonic modes with specific frequencies. The frequency of the collective motions performed by the DBD of MosR in the reduced state to achieve a DNA-binding conformation is in the range of 20 to 50 MHz, but it may be associated to more sporadic events since it requires the combination of a suitable conformation of the N-terminal residues. |
| Databáze: | OpenAIRE |
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