Shedding light on the interaction of human anti-apoptotic Bcl-2 protein with ligands through biophysical and in silico studies

Detalhes bibliográficos
Autor(a) principal: Ramos, João
Data de Publicação: 2019
Outros Autores: Muthukumaran, Jayaraman, Freire, Filipe, Paquete-Ferreira, João, Otrelo-Cardoso, Ana Rita, Svergun, Dmitri, Panjkovich, Alejandro, Santos-Silva, Teresa
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: https://doi.org/10.3390/ijms20040860
Resumo: This work was supported by the Applied Molecular Biosciences Unit-UCIBIO which is financed by national funds from FCT/MCTES (UID/Multi/04378/2019). JM thanks Fundacao para a Ciencia e a Tecnologia (FCT) (SFRH/BPD/97719/2013) Portugal.
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spelling Shedding light on the interaction of human anti-apoptotic Bcl-2 protein with ligands through biophysical and in silico studiesBcl-2BH3 mimeticsBioinformaticsBiophysical methodsCell apoptosisHigh throughput virtual screeningIn silicoProtein-ligand interactionsVenetoclaxCatalysisMolecular BiologySpectroscopyComputer Science ApplicationsPhysical and Theoretical ChemistryOrganic ChemistryInorganic ChemistrySDG 3 - Good Health and Well-beingThis work was supported by the Applied Molecular Biosciences Unit-UCIBIO which is financed by national funds from FCT/MCTES (UID/Multi/04378/2019). JM thanks Fundacao para a Ciencia e a Tecnologia (FCT) (SFRH/BPD/97719/2013) Portugal.Bcl-2 protein is involved in cell apoptosis and is considered an interesting target for anti-cancer therapy. The present study aims to understand the stability and conformational changes of Bcl-2 upon interaction with the inhibitor venetoclax, and to explore other drug-target regions. We combined biophysical and in silico approaches to understand the mechanism of ligand binding to Bcl-2. Thermal shift assay (TSA) and urea electrophoresis showed a significant increase in protein stability upon venetoclax incubation, which is corroborated by molecular docking and molecular dynamics simulations. An 18 °C shift in Bcl-2 melting temperature was observed in the TSA, corresponding to a binding affinity multiple times higher than that of any other reported Bcl-2 inhibitor. This protein-ligand interaction does not implicate alternations in protein conformation, as suggested by SAXS. Additionally, bioinformatics approaches were used to identify deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) of Bcl-2 and their impact on venetoclax binding, suggesting that venetoclax interaction is generally favored against these deleterious nsSNPs. Apart from the BH3 binding groove of Bcl-2, the flexible loop domain (FLD) also plays an important role in regulating the apoptotic process. High-throughput virtual screening (HTVS) identified 5 putative FLD inhibitors from the Zinc database, showing nanomolar affinity toward the FLD of Bcl-2.UCIBIO - Applied Molecular Biosciences UnitDQ - Departamento de QuímicaRUNRamos, JoãoMuthukumaran, JayaramanFreire, FilipePaquete-Ferreira, JoãoOtrelo-Cardoso, Ana RitaSvergun, DmitriPanjkovich, AlejandroSantos-Silva, Teresa2019-09-04T22:40:20Z2019-02-022019-02-02T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://doi.org/10.3390/ijms20040860eng1661-6596PURE: 12898950http://www.scopus.com/inward/record.url?scp=85061864351&partnerID=8YFLogxKhttps://doi.org/10.3390/ijms20040860info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-11T04:35:28Zoai:run.unl.pt:10362/80179Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:35:51.417087Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Shedding light on the interaction of human anti-apoptotic Bcl-2 protein with ligands through biophysical and in silico studies
title Shedding light on the interaction of human anti-apoptotic Bcl-2 protein with ligands through biophysical and in silico studies
spellingShingle Shedding light on the interaction of human anti-apoptotic Bcl-2 protein with ligands through biophysical and in silico studies
Ramos, João
Bcl-2
BH3 mimetics
Bioinformatics
Biophysical methods
Cell apoptosis
High throughput virtual screening
In silico
Protein-ligand interactions
Venetoclax
Catalysis
Molecular Biology
Spectroscopy
Computer Science Applications
Physical and Theoretical Chemistry
Organic Chemistry
Inorganic Chemistry
SDG 3 - Good Health and Well-being
title_short Shedding light on the interaction of human anti-apoptotic Bcl-2 protein with ligands through biophysical and in silico studies
title_full Shedding light on the interaction of human anti-apoptotic Bcl-2 protein with ligands through biophysical and in silico studies
title_fullStr Shedding light on the interaction of human anti-apoptotic Bcl-2 protein with ligands through biophysical and in silico studies
title_full_unstemmed Shedding light on the interaction of human anti-apoptotic Bcl-2 protein with ligands through biophysical and in silico studies
title_sort Shedding light on the interaction of human anti-apoptotic Bcl-2 protein with ligands through biophysical and in silico studies
author Ramos, João
author_facet Ramos, João
Muthukumaran, Jayaraman
Freire, Filipe
Paquete-Ferreira, João
Otrelo-Cardoso, Ana Rita
Svergun, Dmitri
Panjkovich, Alejandro
Santos-Silva, Teresa
author_role author
author2 Muthukumaran, Jayaraman
Freire, Filipe
Paquete-Ferreira, João
Otrelo-Cardoso, Ana Rita
Svergun, Dmitri
Panjkovich, Alejandro
Santos-Silva, Teresa
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv UCIBIO - Applied Molecular Biosciences Unit
DQ - Departamento de Química
RUN
dc.contributor.author.fl_str_mv Ramos, João
Muthukumaran, Jayaraman
Freire, Filipe
Paquete-Ferreira, João
Otrelo-Cardoso, Ana Rita
Svergun, Dmitri
Panjkovich, Alejandro
Santos-Silva, Teresa
dc.subject.por.fl_str_mv Bcl-2
BH3 mimetics
Bioinformatics
Biophysical methods
Cell apoptosis
High throughput virtual screening
In silico
Protein-ligand interactions
Venetoclax
Catalysis
Molecular Biology
Spectroscopy
Computer Science Applications
Physical and Theoretical Chemistry
Organic Chemistry
Inorganic Chemistry
SDG 3 - Good Health and Well-being
topic Bcl-2
BH3 mimetics
Bioinformatics
Biophysical methods
Cell apoptosis
High throughput virtual screening
In silico
Protein-ligand interactions
Venetoclax
Catalysis
Molecular Biology
Spectroscopy
Computer Science Applications
Physical and Theoretical Chemistry
Organic Chemistry
Inorganic Chemistry
SDG 3 - Good Health and Well-being
description This work was supported by the Applied Molecular Biosciences Unit-UCIBIO which is financed by national funds from FCT/MCTES (UID/Multi/04378/2019). JM thanks Fundacao para a Ciencia e a Tecnologia (FCT) (SFRH/BPD/97719/2013) Portugal.
publishDate 2019
dc.date.none.fl_str_mv 2019-09-04T22:40:20Z
2019-02-02
2019-02-02T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv https://doi.org/10.3390/ijms20040860
url https://doi.org/10.3390/ijms20040860
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 1661-6596
PURE: 12898950
http://www.scopus.com/inward/record.url?scp=85061864351&partnerID=8YFLogxK
https://doi.org/10.3390/ijms20040860
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv
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