Functional And Structural Studies Of A Phospholipase A(2)-like Protein Complexed To Zinc Ions: Insights On Its Myotoxicity And Inhibition Mechanism

dc.creatorBorges
dc.creatorRafael J.; Cardoso
dc.creatorFabio F.; Fernandes
dc.creatorCarlos A. H.; Dreyer
dc.creatorThiago R.; de Moraes
dc.creatorDelkia S.; Floriano
dc.creatorRafael S.; Rodrigues-Simioni
dc.creatorLea; Fontes
dc.creatorMarcos R. M.
dc.date2017
dc.datejan
dc.date2017-11-13T13:56:27Z
dc.date2017-11-13T13:56:27Z
dc.date.accessioned2018-03-29T06:09:47Z
dc.date.available2018-03-29T06:09:47Z
dc.identifierBiochimica Et Biophysica Acta-general Subjects. Elsevier Science Bv, v. 1861, p. 3199 - 3209, 2017.
dc.identifier0304-4165
dc.identifier1872-8006
dc.identifierWOS:000390736300028
dc.identifier10.1016/j.bbagen.2016.08.003
dc.identifierhttp://www-sciencedirect-com.ez88.periodicos.capes.gov.br/science/article/pii/S0304416516302847?via%3Dihub
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/329855
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1366880
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.descriptionOne of the main challenges in snakebite envenomation treatment is the development of stable, versatile and efficient and-venom therapies. Local myotoxicity in accidents involving snakes from the Bothrops genus is still a consequence of serum therapy inefficient neutralization that may lead to permanent sequelae in their victims. One of the classes of toxins that participate in muscle necrosis is the PLA(2)-like proteins. The aim of this work was to investigate the role of zinc ions in the inhibition of PLA(2)-like proteins and to advance the current knowledge of their action mechanism. Methods: Myographic and electrophysiological techniques were used to evaluate the inhibitory effect of zinc ions, isothermal titration calorimetry assays were used to measure the affinity between zinc ions and the toxin and Xray crystallography was used to reveal details of this interaction. Results: We demonstrated that zinc ions can effectively inhibit the toxin by the interaction with two different sites, which are related to two different mechanism of inhibition: preventing membrane disruption and impairing the toxin state transition. Furthermore, structural study presented here included an additional step in the current myotoxic mechanism improving the comprehension of the allosteric transition that PLA(2)-like proteins undergo to exert their function. Conclusions: Our findings show that zinc ions are inhibitors of PLA(2)-like proteins and suggest two different mechanisms of inhibition for these ions. General significance: Zinc is a new candidate that can assist in and-venom treatments and can promote the design of new and even more accurate structure-based inhibitors for PLA(2)-like proteins. (C) 2016 Elsevier B.V. All rights reserved.
dc.description1861
dc.description1
dc.description3199
dc.description3209
dc.descriptionFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2015/17286-0, 2013/00873-4]
dc.descriptionConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [300596/2013-8]
dc.descriptionCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES - Brazil) [1592/2011]
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.languageEnglish
dc.publisherElsevier Science BV
dc.publisherAmsterdam
dc.relationBiochimica et Biophysica Acta-General Subjects
dc.rightsfechado
dc.sourceWOS
dc.subjectPla2-like Proteins
dc.subjectSnake Venom
dc.subjectZinc Ions
dc.subjectInhibition By Divalent Ions
dc.subjectMyotoxic Mechanism
dc.subjectX-ray Crystallography
dc.titleFunctional And Structural Studies Of A Phospholipase A(2)-like Protein Complexed To Zinc Ions: Insights On Its Myotoxicity And Inhibition Mechanism
dc.typeArtículos de revistas


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