Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC

Abstract The arginine-agmatine antiporter (AdiC) is a component of an acid resistance system developed by enteric bacteria to resist gastric acidity. In order to avoid neutral proton antiport, the monovalent form of arginine, about as abundant as its divalent form under acidic conditions, should be...

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Autores principales:	Eva-Maria Krammer, Andrew Gibbons, Goedele Roos, Martine Prévost
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Gating Residues Divalent Compounds Agmatine Divalent Ligand Solvation Free Energy Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f35d040aaaeb4c38b8190e9b448e6738
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spelling	oai:doaj.org-article:f35d040aaaeb4c38b8190e9b448e67382021-12-02T15:08:15ZMolecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC10.1038/s41598-018-33963-12045-2322https://doaj.org/article/f35d040aaaeb4c38b8190e9b448e67382018-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-33963-1https://doaj.org/toc/2045-2322Abstract The arginine-agmatine antiporter (AdiC) is a component of an acid resistance system developed by enteric bacteria to resist gastric acidity. In order to avoid neutral proton antiport, the monovalent form of arginine, about as abundant as its divalent form under acidic conditions, should be selectively bound by AdiC for transport into the cytosol. In this study, we shed light on the mechanism through which AdiC distinguishes Arg+ from Arg2+ of arginine by investigating the binding of both forms in addition to that of divalent agmatine, using a combination of molecular dynamics simulations with molecular and quantum mechanics calculations. We show that AdiC indeed preferentially binds Arg+. The weaker binding of divalent compounds results mostly from their greater tendency to remain hydrated than Arg+. Our data suggests that the binding of Arg+ promotes the deprotonation of Glu208, a gating residue, which in turn reinforces its interactions with AdiC, leading to longer residence times of Arg+ in the binding site. Although the total electric charge of the ligand appears to be the determinant factor in the discrimination process, two local interactions formed with Trp293, another gating residue of the binding site, also contribute to the selection mechanism: a cation-π interaction with the guanidinium group of Arg+ and an anion-π interaction involving Glu208.Eva-Maria KrammerAndrew GibbonsGoedele RoosMartine PrévostNature PortfolioarticleGating ResiduesDivalent CompoundsAgmatineDivalent LigandSolvation Free EnergyMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-14 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Gating Residues Divalent Compounds Agmatine Divalent Ligand Solvation Free Energy Medicine R Science Q
spellingShingle	Gating Residues Divalent Compounds Agmatine Divalent Ligand Solvation Free Energy Medicine R Science Q Eva-Maria Krammer Andrew Gibbons Goedele Roos Martine Prévost Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC
description	Abstract The arginine-agmatine antiporter (AdiC) is a component of an acid resistance system developed by enteric bacteria to resist gastric acidity. In order to avoid neutral proton antiport, the monovalent form of arginine, about as abundant as its divalent form under acidic conditions, should be selectively bound by AdiC for transport into the cytosol. In this study, we shed light on the mechanism through which AdiC distinguishes Arg+ from Arg2+ of arginine by investigating the binding of both forms in addition to that of divalent agmatine, using a combination of molecular dynamics simulations with molecular and quantum mechanics calculations. We show that AdiC indeed preferentially binds Arg+. The weaker binding of divalent compounds results mostly from their greater tendency to remain hydrated than Arg+. Our data suggests that the binding of Arg+ promotes the deprotonation of Glu208, a gating residue, which in turn reinforces its interactions with AdiC, leading to longer residence times of Arg+ in the binding site. Although the total electric charge of the ligand appears to be the determinant factor in the discrimination process, two local interactions formed with Trp293, another gating residue of the binding site, also contribute to the selection mechanism: a cation-π interaction with the guanidinium group of Arg+ and an anion-π interaction involving Glu208.
format	article
author	Eva-Maria Krammer Andrew Gibbons Goedele Roos Martine Prévost
author_facet	Eva-Maria Krammer Andrew Gibbons Goedele Roos Martine Prévost
author_sort	Eva-Maria Krammer
title	Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC
title_short	Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC
title_full	Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC
title_fullStr	Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC
title_full_unstemmed	Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC
title_sort	molecular mechanism of substrate selectivity of the arginine-agmatine antiporter adic
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/f35d040aaaeb4c38b8190e9b448e6738
work_keys_str_mv	AT evamariakrammer molecularmechanismofsubstrateselectivityofthearginineagmatineantiporteradic AT andrewgibbons molecularmechanismofsubstrateselectivityofthearginineagmatineantiporteradic AT goedeleroos molecularmechanismofsubstrateselectivityofthearginineagmatineantiporteradic AT martineprevost molecularmechanismofsubstrateselectivityofthearginineagmatineantiporteradic
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Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC

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