Crystal structure of a dimeric Ser49 PLA(2)-like myotoxic component of the Vipera ammodytes meridionalis venomics reveals determinants of myotoxicity and membrane damaging activity

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dc.contributor.authorGeorgieva, Dessislava
dc.contributor.authorCoronado, Monika
dc.contributor.authorOberthuer, Dominik
dc.contributor.authorBuck, Friedrich
dc.contributor.authorDuhalov, Deyan
dc.contributor.authorArni, Raghuvir K. [UNESP]
dc.contributor.authorBetzel, Christian [UNESP]
dc.contributor.institutionUniv Hamburg
dc.contributor.institutionBulgarian Acad Sci
dc.contributor.institutionUniv Med Ctr Hamburg Eppendorf
dc.contributor.institutionBUL BIO NCIPD Ltd
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.date.accessioned2014-05-20T14:02:31Z
dc.date.available2014-05-20T14:02:31Z
dc.date.issued2012-01-01
dc.description.abstractMyotoxicity and membrane damage play a central role in the life-threatening effects of the viper envenomation. Myotoxins are an important part of the viper venomics. A Ser49 PLA(2)-like myotoxin from the venom of Vipera ammodytes meridionalis, the most venomous snake in Europe, was crystallized and its three-dimensional structure determined. The toxin is devoid of phospholipolytic activity. The structure demonstrates a formation of dimers. In the dimers functionally important peptide segments, located on the protein surface, point in the same direction which can strengthen the pharmacological effect. This supports the hypothesis about the physiological importance of the toxin oligomerization for the myotoxicity and membrane damage. The crystallographic model revealed that the structural determinants of myotoxicity (a positively charged C-terminal region and a hydrophobic knuckle) are fully exposed on the protein surface and accessible for interactions with target membranes. Distortion of the catalytic site region explains the absence of enzymatic activity. The structure reveals anion-binding sites which can be considered as possible sites of interactions of the toxin with a negatively charged membrane surface. The high structural similarity of the Ser49 myotoxin and Asp49 PLA(2) from the same venom suggests an evolutionary relationship: probably, the Ser49 myotoxin is a product of evolution of the catalytically active phospholipase A(2). The first toxin lost the enzymatic activity which is not necessary for the myotoxicity but preserved the cytotoxicity and membrane damaging activity as important components of the venom toxicity.en
dc.description.affiliationUniv Hamburg, Lab Struct Biol Infect & Inflammat, DESY, Inst Biochem & Mol Biol, D-22603 Hamburg, Germany
dc.description.affiliationBulgarian Acad Sci, Inst Organ Chem, BU-1113 Sofia, Bulgaria
dc.description.affiliationUniv Med Ctr Hamburg Eppendorf, Inst Clin Chem, D-20246 Hamburg, Germany
dc.description.affiliationBUL BIO NCIPD Ltd, Sofia, Bulgaria
dc.description.affiliationUniv Estadual Paulista UNESP, Dept Fis, Ctr Multiusuario Inovacao Biomol, BR-15054000 Sao Jose do Rio Preto, SP, Brazil
dc.description.affiliationUnespUniv Estadual Paulista UNESP, Dept Fis, Ctr Multiusuario Inovacao Biomol, BR-15054000 Sao Jose do Rio Preto, SP, Brazil
dc.description.sponsorshipDeutsche Forschungsgemeinschaft (DFG)
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipDeutscher Akademischer Austauschdienst (DAAD)
dc.description.sponsorshipBulgarian National Foundation for Scientific Research
dc.description.sponsorshipIdDFG: BE 1443-18-1
dc.description.sponsorshipIdCAPES: 80563/2911
dc.description.sponsorshipIdDAAD (PROBAL): 50754442
dc.description.sponsorshipIdBulgarian National Foundation for Scientific Research: TK-B-1610/06
dc.format.extent1405-1411
dc.identifierhttp://dx.doi.org/10.1039/c2mb05490f
dc.identifier.citationMolecular Biosystems. Cambridge: Royal Soc Chemistry, v. 8, n. 5, p. 1405-1411, 2012.
dc.identifier.doi10.1039/c2mb05490f
dc.identifier.issn1742-206X
dc.identifier.lattes9162508978945887
dc.identifier.orcid0000-0003-2460-1145
dc.identifier.urihttp://hdl.handle.net/11449/22037
dc.identifier.wosWOS:000302368600003
dc.language.isoeng
dc.publisherRoyal Soc Chemistry
dc.relation.ispartofMolecular Biosystems
dc.relation.ispartofjcr2.759
dc.rights.accessRightsAcesso restrito
dc.sourceWeb of Science
dc.titleCrystal structure of a dimeric Ser49 PLA(2)-like myotoxic component of the Vipera ammodytes meridionalis venomics reveals determinants of myotoxicity and membrane damaging activityen
dc.typeArtigo
dcterms.licensehttp://www.rsc.org/AboutUs/Copyright/Authordeposition.asp
dcterms.rightsHolderRoyal Soc Chemistry
unesp.author.lattes9162508978945887[6]
unesp.author.orcid0000-0003-2460-1145[6]
unesp.campusUniversidade Estadual Paulista (Unesp), Instituto de Biociências Letras e Ciências Exatas, São José do Rio Pretopt

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