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https://hdl.handle.net/10316/105289
Título: | Transcription factor allosteric regulation through substrate coordination to zinc | Autor: | Almeida, Beatriz C. Kaczmarek, Jennifer A. Figueiredo, Pedro Prather, Kristala L. J. Carvalho, Alexandra T. P. |
Data: | Jun-2021 | Editora: | Oxford University Press | Projeto: | MIT-Portugal seed project 6937814 UIDB/04539/2020 IF/01272/2015 SFRH/BD/144303/2019 SFRH/BD/150697/2020 |
Título da revista, periódico, livro ou evento: | NAR Genomics and Bioinformatics | Volume: | 3 | Número: | 2 | Resumo: | The development of new synthetic biology circuits for biotechnology and medicine requires deeper mechanistic insight into allosteric transcription factors (aTFs). Here we studied the aTF UxuR, a homodimer of two domains connected by a highly flexible linker region. To explore how ligand binding to UxuR affects protein dynamics we performed molecular dynamics simulations in the free protein, the aTF bound to the inducer D-fructuronate or the structural isomer D-glucuronate. We then validated our results by constructing a sensor plasmid for D-fructuronate in Escherichia coli and performed site-directed mutagenesis. Our results show that zinc coordination is necessary for UxuR function since mutation to alanines prevents expression de-repression by D-fructuronate. Analyzing the different complexes, we found that the disordered linker regions allow the N-terminal domains to display fast and large movements. When the inducer is bound, UxuR can sample an open conformation with a more pronounced negative charge at the surface of the N-terminal DNA binding domains. In opposition, in the free and D-glucuronate bond forms the protein samples closed conformations, with a more positive character at the surface of the DNA binding regions. These molecular insights provide a new basis to harness these systems for biological systems engineering. | URI: | https://hdl.handle.net/10316/105289 | ISSN: | 2631-9268 | DOI: | 10.1093/nargab/lqab033 | Direitos: | openAccess |
Aparece nas coleções: | I&D CNC - Artigos em Revistas Internacionais |
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Transcription factor allosteric regulation through substrate coordination to zinc.pdf | 6.89 MB | Adobe PDF | Ver/Abrir |
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