Rigidity of loop 1 contributes to equipotency of globular and ribbon isomers of α-conotoxin AusIA

Abstract α-Conotoxins are small disulfide-rich peptides targeting nicotinic acetylcholine receptors (nAChRs) characterised by a CICII-Xm-CIII-Xn-CIV framework that invariably adopt the native globular conformations which is typically most potent. α-Conotoxins are divided into several structural subg...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Thao N. T. Ho, Nikita Abraham, Richard J. Lewis
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/90cdf3a5ccdd43e1b090a6de1b268a4b
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:90cdf3a5ccdd43e1b090a6de1b268a4b
record_format	dspace
spelling	oai:doaj.org-article:90cdf3a5ccdd43e1b090a6de1b268a4b2021-11-14T12:22:58ZRigidity of loop 1 contributes to equipotency of globular and ribbon isomers of α-conotoxin AusIA10.1038/s41598-021-01277-42045-2322https://doaj.org/article/90cdf3a5ccdd43e1b090a6de1b268a4b2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-01277-4https://doaj.org/toc/2045-2322Abstract α-Conotoxins are small disulfide-rich peptides targeting nicotinic acetylcholine receptors (nAChRs) characterised by a CICII-Xm-CIII-Xn-CIV framework that invariably adopt the native globular conformations which is typically most potent. α-Conotoxins are divided into several structural subgroups based on the number of residues within the two loops braced by the disulfide bonds (m/n), with the 4/7 and 4/3 subgroups dominating. AusIA is a relatively rare α5/5-conotoxin isolated from the venom of Conus australis. Surprisingly, the ribbon isomer displayed equipotency to the wild-type globular AusIA at human α7-containing nAChR. To understand the molecular basis for equipotency, we determined the co-crystal structures of both isomers at Lymnea stagnalis acetylcholine binding protein. The additional residue in the first loop of AusIA was found to be a critical determinant of equipotency, with 11-fold and 86-fold shifts in potency in favour of globular AusIA over ribbon AusIA observed following deletion of Ala4 or Arg5, respectively. This divergence in the potency between globular AusIA and ribbon AusIA was further enhanced upon truncation of the non-conserved Val at the C-termini. Conversely, equipotency could be replicated in LsIA and TxIA [A10L] following insertion of an Ala in the first loop. These findings provide a new understanding of the role the first loop in ribbon and globular α-conotoxins can play in directing α-conotoxin nAChR pharmacology.Thao N. T. HoNikita AbrahamRichard J. LewisNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Thao N. T. Ho Nikita Abraham Richard J. Lewis Rigidity of loop 1 contributes to equipotency of globular and ribbon isomers of α-conotoxin AusIA
description	Abstract α-Conotoxins are small disulfide-rich peptides targeting nicotinic acetylcholine receptors (nAChRs) characterised by a CICII-Xm-CIII-Xn-CIV framework that invariably adopt the native globular conformations which is typically most potent. α-Conotoxins are divided into several structural subgroups based on the number of residues within the two loops braced by the disulfide bonds (m/n), with the 4/7 and 4/3 subgroups dominating. AusIA is a relatively rare α5/5-conotoxin isolated from the venom of Conus australis. Surprisingly, the ribbon isomer displayed equipotency to the wild-type globular AusIA at human α7-containing nAChR. To understand the molecular basis for equipotency, we determined the co-crystal structures of both isomers at Lymnea stagnalis acetylcholine binding protein. The additional residue in the first loop of AusIA was found to be a critical determinant of equipotency, with 11-fold and 86-fold shifts in potency in favour of globular AusIA over ribbon AusIA observed following deletion of Ala4 or Arg5, respectively. This divergence in the potency between globular AusIA and ribbon AusIA was further enhanced upon truncation of the non-conserved Val at the C-termini. Conversely, equipotency could be replicated in LsIA and TxIA [A10L] following insertion of an Ala in the first loop. These findings provide a new understanding of the role the first loop in ribbon and globular α-conotoxins can play in directing α-conotoxin nAChR pharmacology.
format	article
author	Thao N. T. Ho Nikita Abraham Richard J. Lewis
author_facet	Thao N. T. Ho Nikita Abraham Richard J. Lewis
author_sort	Thao N. T. Ho
title	Rigidity of loop 1 contributes to equipotency of globular and ribbon isomers of α-conotoxin AusIA
title_short	Rigidity of loop 1 contributes to equipotency of globular and ribbon isomers of α-conotoxin AusIA
title_full	Rigidity of loop 1 contributes to equipotency of globular and ribbon isomers of α-conotoxin AusIA
title_fullStr	Rigidity of loop 1 contributes to equipotency of globular and ribbon isomers of α-conotoxin AusIA
title_full_unstemmed	Rigidity of loop 1 contributes to equipotency of globular and ribbon isomers of α-conotoxin AusIA
title_sort	rigidity of loop 1 contributes to equipotency of globular and ribbon isomers of α-conotoxin ausia
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/90cdf3a5ccdd43e1b090a6de1b268a4b
work_keys_str_mv	AT thaontho rigidityofloop1contributestoequipotencyofglobularandribbonisomersofaconotoxinausia AT nikitaabraham rigidityofloop1contributestoequipotencyofglobularandribbonisomersofaconotoxinausia AT richardjlewis rigidityofloop1contributestoequipotencyofglobularandribbonisomersofaconotoxinausia
_version_	1718429243212300288

Rigidity of loop 1 contributes to equipotency of globular and ribbon isomers of α-conotoxin AusIA

Ejemplares similares