Ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins

Abstract Mamba venoms contain a multiplicity of three-finger fold aminergic toxins known to interact with various α-adrenergic, muscarinic and dopaminergic receptors with different pharmacological profiles. In order to generate novel functions on this structural scaffold and to avoid the daunting ta...

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Autores principales:	Guillaume Blanchet, Doria Alili, Adèle Protte, Gregory Upert, Nicolas Gilles, Livia Tepshi, Enrico A. Stura, Gilles Mourier, Denis Servent
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6cf6bae70a12426a85f6c165e6b9fabf
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spelling	oai:doaj.org-article:6cf6bae70a12426a85f6c165e6b9fabf2021-12-02T12:30:54ZAncestral protein resurrection and engineering opportunities of the mamba aminergic toxins10.1038/s41598-017-02953-02045-2322https://doaj.org/article/6cf6bae70a12426a85f6c165e6b9fabf2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02953-0https://doaj.org/toc/2045-2322Abstract Mamba venoms contain a multiplicity of three-finger fold aminergic toxins known to interact with various α-adrenergic, muscarinic and dopaminergic receptors with different pharmacological profiles. In order to generate novel functions on this structural scaffold and to avoid the daunting task of producing and screening an overwhelming number of variants generated by a classical protein engineering strategy, we accepted the challenge of resurrecting ancestral proteins, likely to have possessed functional properties. This innovative approach that exploits molecular evolution models to efficiently guide protein engineering, has allowed us to generate a small library of six ancestral toxin (AncTx) variants and associate their pharmacological profiles to key functional substitutions. Among these variants, we identified AncTx1 as the most α1A-adrenoceptor selective peptide known to date and AncTx5 as the most potent inhibitor of the three α2 adrenoceptor subtypes. Three positions in the ρ-Da1a evolutionary pathway, positions 28, 38 and 43 have been identified as key modulators of the affinities for the α1 and α2C adrenoceptor subtypes. Here, we present a first attempt at rational engineering of the aminergic toxins, revealing an epistasis phenomenon.Guillaume BlanchetDoria AliliAdèle ProtteGregory UpertNicolas GillesLivia TepshiEnrico A. SturaGilles MourierDenis ServentNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Guillaume Blanchet Doria Alili Adèle Protte Gregory Upert Nicolas Gilles Livia Tepshi Enrico A. Stura Gilles Mourier Denis Servent Ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins
description	Abstract Mamba venoms contain a multiplicity of three-finger fold aminergic toxins known to interact with various α-adrenergic, muscarinic and dopaminergic receptors with different pharmacological profiles. In order to generate novel functions on this structural scaffold and to avoid the daunting task of producing and screening an overwhelming number of variants generated by a classical protein engineering strategy, we accepted the challenge of resurrecting ancestral proteins, likely to have possessed functional properties. This innovative approach that exploits molecular evolution models to efficiently guide protein engineering, has allowed us to generate a small library of six ancestral toxin (AncTx) variants and associate their pharmacological profiles to key functional substitutions. Among these variants, we identified AncTx1 as the most α1A-adrenoceptor selective peptide known to date and AncTx5 as the most potent inhibitor of the three α2 adrenoceptor subtypes. Three positions in the ρ-Da1a evolutionary pathway, positions 28, 38 and 43 have been identified as key modulators of the affinities for the α1 and α2C adrenoceptor subtypes. Here, we present a first attempt at rational engineering of the aminergic toxins, revealing an epistasis phenomenon.
format	article
author	Guillaume Blanchet Doria Alili Adèle Protte Gregory Upert Nicolas Gilles Livia Tepshi Enrico A. Stura Gilles Mourier Denis Servent
author_facet	Guillaume Blanchet Doria Alili Adèle Protte Gregory Upert Nicolas Gilles Livia Tepshi Enrico A. Stura Gilles Mourier Denis Servent
author_sort	Guillaume Blanchet
title	Ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins
title_short	Ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins
title_full	Ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins
title_fullStr	Ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins
title_full_unstemmed	Ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins
title_sort	ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/6cf6bae70a12426a85f6c165e6b9fabf
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Ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins

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