Modelling the active SARS-CoV-2 helicase complex as a basis for structure-based inhibitor design
| Autor: | Sarah A. Harris, Geoff Wells, Pedro J. Buigues, Magd Badaoui, Sam Alexander Martino, Andrei V. Pisliakov, Dénes Berta, Nadia Elghobashi-Meinhardt, Elisa Frezza, Edina Rosta |
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| Přispěvatelé: | Cibles Thérapeutiques et conception de médicaments (CiTCoM - UMR 8038), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP) |
| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
0303 health sciences biology Chemistry Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Allosteric regulation Helicase General Chemistry Computational biology 010402 general chemistry biology.organism_classification 01 natural sciences RNA Helicase A 0104 chemical sciences 3. Good health [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry 03 medical and health sciences Molecular dynamics Enzyme Viral replication biology.protein Coronaviridae 030304 developmental biology |
| Zdroj: | Chemical Science Chemical Science, The Royal Society of Chemistry, 2021, ⟨10.1039/D1SC02775A⟩ |
| ISSN: | 2041-6520 2041-6539 |
| DOI: | 10.1039/D1SC02775A⟩ |
| Popis: | The RNA helicase (non-structural protein 13, NSP13) of SARS-CoV-2 is essential for viral replication, and it is highly conserved among the coronaviridae family, thus a prominent drug target to treat COVID-19. We present here structural models and dynamics of the helicase in complex with its native substrates based on thorough analysis of homologous sequences and existing experimental structures. We performed and analysed microseconds of molecular dynamics (MD) simulations, and our model provides valuable insights to the binding of the ATP and ssRNA at the atomic level. We identify the principal motions characterising the enzyme and highlight the effect of the natural substrates on this dynamics. Furthermore, allosteric binding sites are suggested by our pocket analysis. Our obtained structural and dynamical insights are important for subsequent studies of the catalytic function and for the development of specific inhibitors at our characterised binding pockets for this promising COVID-19 drug target. The RNA helicase (non-structural protein 13, NSP13) of SARS-CoV-2 is essential for viral replication, and it is highly conserved among the coronaviridae family, thus a prominent drug target to treat COVID-19. |
| Databáze: | OpenAIRE |
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