Crystal structure of a phospholipase A(2) homolog complexed with p-bromophenacyl bromide reveals important structural changes associated with the inhibition of myotoxic activity

dc.contributorUniversidade Estadual Paulista (UNESP)
dc.creatorMarchi-Salvador, Daniela P.
dc.creatorFernandes, Carlos A. H.
dc.creatorSilveira, Lucas B.
dc.creatorSoares, Andreimar M.
dc.creatorFontes, Marcos R. M.
dc.date2014-05-20T13:49:35Z
dc.date2016-10-25T17:02:01Z
dc.date2014-05-20T13:49:35Z
dc.date2016-10-25T17:02:01Z
dc.date2009-11-01
dc.date.accessioned2017-04-05T21:01:37Z
dc.date.available2017-04-05T21:01:37Z
dc.identifierBiochimica Et Biophysica Acta-proteins and Proteomics. Amsterdam: Elsevier B.V., v. 1794, n. 11, p. 1583-1590, 2009.
dc.identifier1570-9639
dc.identifierhttp://hdl.handle.net/11449/17681
dc.identifierhttp://acervodigital.unesp.br/handle/11449/17681
dc.identifier10.1016/j.bbapap.2009.07.005
dc.identifierWOS:000270763900005
dc.identifierhttp://dx.doi.org/10.1016/j.bbapap.2009.07.005
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/864106
dc.descriptionFor the first time, the structure of a catalytic inactive phospholipase A(2) homolog (Lys49-PLA(2)s) complexed with p-bromophenacyl bromide (BPB) has been solved by X-ray crystallography. Lys49-PLA(2)s are among the main components of Viperidae snake venoms, causing myonecrosis and other actions despite their catalytic inactivity. BPB, a classic inhibitor of catalytic-active PLA(2)s, has been used since the 1970s because it binds specifically the His48 residue of the catalytic site. Curiously, when Lys49-PLA(2) is chemically modified by BPB, it causes a partial inhibition of the myotoxic function which is associated with the C-terminus and not with the catalytic site. The structure of PrTX-I complexed to BPB revealed unambiguously that the inhibitor binds covalently to His48, causing a distortion of the Ca2+-binding loop region and C-terminus rearrangement in one of its monomers. The comparison between the apo and BPB-complexed PrTX-I structures showed an increased symmetry between the two monomers with the formation of an interchain hydrogen bond between Tyr119 residues. PrTX-I undergoes tertiary and quaternary structural changes when complexed to BPB which could be related to reduction of myotoxicity and other toxic activities. We also proposed a novel myotoxic inhibition hypothesis integrating "myotoxic" and "active" sites for bothropic Lys49-PLA(2)s. (C) 2009 Elsevier B.V. All rights reserved.
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.languageeng
dc.publisherElsevier B.V.
dc.relationBiochimica et Biophysica Acta: Proteins and Proteomics
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.subjectPhospholipase A(2) homolog
dc.subjectBothrops pirajai venom
dc.subjectMyotoxicity
dc.subjectp-Bromophenacyl bromide inhibitor
dc.subjectX-ray crystallography
dc.titleCrystal structure of a phospholipase A(2) homolog complexed with p-bromophenacyl bromide reveals important structural changes associated with the inhibition of myotoxic activity
dc.typeOtro


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