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https://hdl.handle.net/1822/73598
Título: | The milk-derived lactoferrin inhibits V-ATPase activity by targeting its V1 domain |
Autor(es): | Pereira, Cátia Sofia Santos Rocha, Juliana F. Fernandes, Henrique S. Rodrigues, L. R. Côrte-Real, Manuela Sousa, Sérgio F. |
Palavras-chave: | Lactoferrin V-ATPase Docking Molecular dynamics |
Data: | Set-2021 |
Editora: | Elsevier |
Revista: | International Journal of Biological Macromolecules |
Citação: | Cátia S. Pereira; Rocha, Juliana F.; Fernandes, Henrique S.; Rodrigues, Lígia R.; Côrte-Real, Manuela; Sousa, Sérgio F., The milk-derived lactoferrin inhibits V-ATPase activity by targeting its V1 domain. International Journal of Biological Macromolecules, 186, 54-70, 2021 |
Resumo(s): | Lactoferrin (Lf), a bioactive milk protein, exhibits strong anticancer and antifungal activities. The search for Lf targets and mechanisms of action is of utmost importance to enhance its effective applications. A common feature among Lf-treated cancer and fungal cells is the inhibition of a proton pump called V-ATPase. Lf-driven V-ATPase inhibition leads to cytosolic acidification, ultimately causing cell death of cancer and fungal cells. Given that a detailed elucidation of how Lf and V-ATPase interact is still missing, herein we aimed to fill this gap by employing a five-stage computational approach. Molecular dynamics simulations of both proteins were performed to obtain a robust sampling of their conformational landscape, followed by clustering, which allowed retrieving representative structures, to then perform protein-protein docking. Subsequently, molecular dynamics simulations of the docked complexes and free binding energy calculations were carried out to evaluate the dynamic binding process and build a final ranking based on the binding affinities. Detailed atomist analysis of the top ranked complexes clearly indicates that Lf binds to the V1 cytosolic domain of V-ATPase. Particularly, our data suggest that Lf binds to the interfaces between A/B subunits, where the ATP hydrolysis occurs, thus inhibiting this process. The free energy decomposition analysis further identified key binding residues that will certainly aid in the rational design of follow-up experimental studies, hence bridging computational and experimental biochemistry. |
Tipo: | Artigo |
URI: | https://hdl.handle.net/1822/73598 |
DOI: | 10.1016/j.ijbiomac.2021.06.200 |
ISSN: | 0141-8130 |
Versão da editora: | http://www.elsevier.com/locate/issn/01418130 |
Arbitragem científica: | yes |
Acesso: | Acesso restrito UMinho |
Aparece nas coleções: | CEB - Publicações em Revistas/Séries Internacionais / Publications in International Journals/Series |
Ficheiros deste registo:
Ficheiro | Descrição | Tamanho | Formato | |
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document_54520_1.pdf Acesso restrito! | 11,69 MB | Adobe PDF | Ver/Abrir |