A Biologically-validated HCV E1E2 Heterodimer Structural Model

Abstract The design of vaccine strategies and the development of drugs targeting the early stages of Hepatitis C virus (HCV) infection are hampered by the lack of structural information about its surface glycoproteins E1 and E2, the two constituents of HCV entry machinery. Despite the recent crystal...

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Autores principales:	Matteo Castelli, Nicola Clementi, Jennifer Pfaff, Giuseppe A. Sautto, Roberta A. Diotti, Roberto Burioni, Benjamin J. Doranz, Matteo Dal Peraro, Massimo Clementi, Nicasio Mancini
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/563bbbe9e5ee45d1a8b0876740226501
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spelling	oai:doaj.org-article:563bbbe9e5ee45d1a8b08767402265012021-12-02T15:05:50ZA Biologically-validated HCV E1E2 Heterodimer Structural Model10.1038/s41598-017-00320-72045-2322https://doaj.org/article/563bbbe9e5ee45d1a8b08767402265012017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00320-7https://doaj.org/toc/2045-2322Abstract The design of vaccine strategies and the development of drugs targeting the early stages of Hepatitis C virus (HCV) infection are hampered by the lack of structural information about its surface glycoproteins E1 and E2, the two constituents of HCV entry machinery. Despite the recent crystal resolution of limited versions of both proteins in truncated form, a complete picture of the E1E2 complex is still missing. Here we combined deep computational analysis of E1E2 secondary, tertiary and quaternary structure with functional and immunological mutational analysis across E1E2 in order to propose an in silico model for the ectodomain of the E1E2 heterodimer. Our model describes E1-E2 ectodomain dimerization interfaces, provides a structural explanation of E1 and E2 immunogenicity and sheds light on the molecular processes and disulfide bridges isomerization underlying the conformational changes required for fusion. Comprehensive alanine mutational analysis across 553 residues of E1E2 also resulted in identifying the epitope maps of diverse mAbs and the disulfide connectivity underlying E1E2 native conformation. The predicted structure unveils E1 and E2 structures in complex, thus representing a step towards the rational design of immunogens and drugs inhibiting HCV entry.Matteo CastelliNicola ClementiJennifer PfaffGiuseppe A. SauttoRoberta A. DiottiRoberto BurioniBenjamin J. DoranzMatteo Dal PeraroMassimo ClementiNicasio ManciniNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Matteo Castelli Nicola Clementi Jennifer Pfaff Giuseppe A. Sautto Roberta A. Diotti Roberto Burioni Benjamin J. Doranz Matteo Dal Peraro Massimo Clementi Nicasio Mancini A Biologically-validated HCV E1E2 Heterodimer Structural Model
description	Abstract The design of vaccine strategies and the development of drugs targeting the early stages of Hepatitis C virus (HCV) infection are hampered by the lack of structural information about its surface glycoproteins E1 and E2, the two constituents of HCV entry machinery. Despite the recent crystal resolution of limited versions of both proteins in truncated form, a complete picture of the E1E2 complex is still missing. Here we combined deep computational analysis of E1E2 secondary, tertiary and quaternary structure with functional and immunological mutational analysis across E1E2 in order to propose an in silico model for the ectodomain of the E1E2 heterodimer. Our model describes E1-E2 ectodomain dimerization interfaces, provides a structural explanation of E1 and E2 immunogenicity and sheds light on the molecular processes and disulfide bridges isomerization underlying the conformational changes required for fusion. Comprehensive alanine mutational analysis across 553 residues of E1E2 also resulted in identifying the epitope maps of diverse mAbs and the disulfide connectivity underlying E1E2 native conformation. The predicted structure unveils E1 and E2 structures in complex, thus representing a step towards the rational design of immunogens and drugs inhibiting HCV entry.
format	article
author	Matteo Castelli Nicola Clementi Jennifer Pfaff Giuseppe A. Sautto Roberta A. Diotti Roberto Burioni Benjamin J. Doranz Matteo Dal Peraro Massimo Clementi Nicasio Mancini
author_facet	Matteo Castelli Nicola Clementi Jennifer Pfaff Giuseppe A. Sautto Roberta A. Diotti Roberto Burioni Benjamin J. Doranz Matteo Dal Peraro Massimo Clementi Nicasio Mancini
author_sort	Matteo Castelli
title	A Biologically-validated HCV E1E2 Heterodimer Structural Model
title_short	A Biologically-validated HCV E1E2 Heterodimer Structural Model
title_full	A Biologically-validated HCV E1E2 Heterodimer Structural Model
title_fullStr	A Biologically-validated HCV E1E2 Heterodimer Structural Model
title_full_unstemmed	A Biologically-validated HCV E1E2 Heterodimer Structural Model
title_sort	biologically-validated hcv e1e2 heterodimer structural model
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/563bbbe9e5ee45d1a8b0876740226501
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A Biologically-validated HCV E1E2 Heterodimer Structural Model

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