Structural Basis for Cyclosporin Isoform-Specific Inhibition of Cyclophilins from Toxoplasma gondii

13 pags., 7 figs., 4 tabs.

Detalles Bibliográficos
Autores: Favretto, Filippo, Jiménez-Faraco, Eva, Conter, Carolina, Dominici, Paola, Hermoso, Juan A., Astegno, Alessandra
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/295965
Acceso en línea:http://hdl.handle.net/10261/295965
https://api.elsevier.com/content/abstract/scopus_id/85146563648
Access Level:acceso abierto
Palabra clave:Toxoplasma gondii
Chaperone-like activity
Crystal structure
Cyclophilin
Cyclosporin
Peptidyl-prolyl isomerization
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spelling Structural Basis for Cyclosporin Isoform-Specific Inhibition of Cyclophilins from Toxoplasma gondiiFavretto, FilippoJiménez-Faraco, EvaConter, CarolinaDominici, PaolaHermoso, Juan A.Astegno, AlessandraToxoplasma gondiiChaperone-like activityCrystal structureCyclophilinCyclosporinPeptidyl-prolyl isomerization13 pags., 7 figs., 4 tabs.Cyclosporin (CsA) has antiparasite activity against the human pathogen Toxoplasma gondii. A possible mechanism of action involves CsA binding to T. gondii cyclophilins, although much remains to be understood. Herein, we characterize the functional and structural properties of a conserved (TgCyp23) and a more divergent (TgCyp18.4) cyclophilin isoform from T. gondii. While TgCyp23 is a highly active cis-trans-prolyl isomerase (PPIase) and binds CsA with nanomolar affinity, TgCyp18.4 shows low PPIase activity and is significantly less sensitive to CsA inhibition. The crystal structure of the TgCyp23:CsA complex was solved at the atomic resolution showing the molecular details of CsA recognition by the protein. Computational and structural studies revealed relevant differences at the CsA-binding site between TgCyp18.4 and TgCyp23, suggesting that the two cyclophilins might have distinct functions in the parasite. These studies highlight the extensive diversification of TgCyps and pave the way for antiparasite interventions based on selective targeting of cyclophilins.This research was supported by departmental funds provided by the Italian Minister of University and Research (FUR2021) to A.A. and P.D. and in part by the Italian MIUR-PRIN 2017 Grant No. 2017ZBBYNC to A.A. The work in Spain was funded by grant PID2020-115331GB-100 from the Spanish Ministry of Science and Innovation to J.A.H. The authors thank Dr. Javier Oroz for providing the synthetic gene coding for CypA. They also thank the Centro Piattaforme Tecnologiche of the University of Verona for providing access to the spectroscopic platform.Peer reviewedAmerican Chemical SocietyMinistero dell'Istruzione, dell'Università e della RicercaMinisterio de Ciencia e Innovación (España)Università degli Studi di VeronaJiménez-Faraco, Eva [0000-0002-5548-3252]Hermoso, Juan A. [0000-0002-1862-8950]Astegno, Alessandra [0000-0002-7341-0970]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202320232023info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/295965https://api.elsevier.com/content/abstract/scopus_id/85146563648reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-115331GB-I00ACS infectious diseaseshttps://doi.org/10.1021/acsinfecdis.2c00566Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2959652026-05-22T06:33:51Z
dc.title.none.fl_str_mv Structural Basis for Cyclosporin Isoform-Specific Inhibition of Cyclophilins from Toxoplasma gondii
title Structural Basis for Cyclosporin Isoform-Specific Inhibition of Cyclophilins from Toxoplasma gondii
spellingShingle Structural Basis for Cyclosporin Isoform-Specific Inhibition of Cyclophilins from Toxoplasma gondii
Favretto, Filippo
Toxoplasma gondii
Chaperone-like activity
Crystal structure
Cyclophilin
Cyclosporin
Peptidyl-prolyl isomerization
title_short Structural Basis for Cyclosporin Isoform-Specific Inhibition of Cyclophilins from Toxoplasma gondii
title_full Structural Basis for Cyclosporin Isoform-Specific Inhibition of Cyclophilins from Toxoplasma gondii
title_fullStr Structural Basis for Cyclosporin Isoform-Specific Inhibition of Cyclophilins from Toxoplasma gondii
title_full_unstemmed Structural Basis for Cyclosporin Isoform-Specific Inhibition of Cyclophilins from Toxoplasma gondii
title_sort Structural Basis for Cyclosporin Isoform-Specific Inhibition of Cyclophilins from Toxoplasma gondii
dc.creator.none.fl_str_mv Favretto, Filippo
Jiménez-Faraco, Eva
Conter, Carolina
Dominici, Paola
Hermoso, Juan A.
Astegno, Alessandra
author Favretto, Filippo
author_facet Favretto, Filippo
Jiménez-Faraco, Eva
Conter, Carolina
Dominici, Paola
Hermoso, Juan A.
Astegno, Alessandra
author_role author
author2 Jiménez-Faraco, Eva
Conter, Carolina
Dominici, Paola
Hermoso, Juan A.
Astegno, Alessandra
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Ministero dell'Istruzione, dell'Università e della Ricerca
Ministerio de Ciencia e Innovación (España)
Università degli Studi di Verona
Jiménez-Faraco, Eva [0000-0002-5548-3252]
Hermoso, Juan A. [0000-0002-1862-8950]
Astegno, Alessandra [0000-0002-7341-0970]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Toxoplasma gondii
Chaperone-like activity
Crystal structure
Cyclophilin
Cyclosporin
Peptidyl-prolyl isomerization
topic Toxoplasma gondii
Chaperone-like activity
Crystal structure
Cyclophilin
Cyclosporin
Peptidyl-prolyl isomerization
description 13 pags., 7 figs., 4 tabs.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/295965
https://api.elsevier.com/content/abstract/scopus_id/85146563648
url http://hdl.handle.net/10261/295965
https://api.elsevier.com/content/abstract/scopus_id/85146563648
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-115331GB-I00
ACS infectious diseases
https://doi.org/10.1021/acsinfecdis.2c00566
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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