Active and exo-site inhibition of human factor Xa: Structure of des-Gla factor Xa inhibited by NAP5, a potent nematode anticoagulant protein from Ancylostoma caninum

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dc.contributor.authorRios-Steiner, Jorge L.
dc.contributor.authorMurakami, Mario T.
dc.contributor.authorTulinsky, Alexander
dc.contributor.authorArni, Raghuvir K.
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionMichigan State University
dc.contributor.institutionCtr Appl Toxinol CAT CEPID
dc.date.accessioned2014-05-20T15:23:22Z
dc.date.available2014-05-20T15:23:22Z
dc.date.issued2007-08-17
dc.description.abstractHookworms are hematophagous nematodes capable of growth, development and subsistence in living host systems such as humans and other mammals. Approximately one billion, or one in six, people worldwide are infected by hookworms causing gastrointestinal blood loss and iron deficiency anemia. The hematophagous hookworm Ancylostoma caninum produces a family of small, disulfide-linked protein anticoagulants (75-84 amino acid residues). One of these nematode anticoagulant proteins, NAP5, inhibits the amidolytic activity of factor Xa (fXa) with K-i = 43 pM, and is the most potent natural fXa inhibitor identified thus far. The crystal structure of NAP5 bound at the active site of gamma-carboxyglutamic acid domainless factor Xa (des-fXa) has been determined at 3.1 angstrom resolution, which indicates that Asp189 (fXa, S1 subsite) binds to Arg40 (NAP5, P1 site) in a mode similar to that of the BPTI/trypsin interaction. However, the hydroxyl group of Ser39 of NAP5 additionally forms a hydrogen bond (2.5 angstrom) with His57 NE2 of the catalytic triad, replacing the hydrogen bond of Ser195 OG to the latter in the native structure, resulting in an interaction that has not been observed before. Furthermore, the C-terminal extension of NAP5 surprisingly interacts with the fXa exosite of a symmetry-equivalent molecule forming a short intermolecular beta-strand as observed in the structure of the NAPc2/fXa complex. This indicates that NAP5 can bind to fXa at the active site, or the exosite, and to fX at the exosite. However, unlike NAPc2, NAP5 does not inhibit fVIIa of the fVIIa/TF complex. (c) 2007 Elsevier Ltd. All rights reserved.en
dc.description.affiliationUNESP, Dept Phys, BR-15054000 Sao Jose do Rio Preto, Brazil
dc.description.affiliationMichigan State Univ, Dept Chem, E Lansing, MI 48824 USA
dc.description.affiliationCtr Appl Toxinol CAT CEPID, BR-05503900 São Paulo, Brazil
dc.description.affiliationUNESP, Ctr Struct Genom, BR-15054000 Sao Jose do Rio Preto, Brazil
dc.description.affiliationUnespUNESP, Dept Phys, BR-15054000 Sao Jose do Rio Preto, Brazil
dc.description.affiliationUnespUNESP, Ctr Struct Genom, BR-15054000 Sao Jose do Rio Preto, Brazil
dc.format.extent774-786
dc.identifierhttp://dx.doi.org/10.1016/j.jmb.2007.05.042
dc.identifier.citationJournal of Molecular Biology. London: Academic Press Ltd Elsevier B.V. Ltd, v. 371, n. 3, p. 774-786, 2007.
dc.identifier.doi10.1016/j.jmb.2007.05.042
dc.identifier.issn0022-2836
dc.identifier.lattes9162508978945887
dc.identifier.orcid0000-0003-2460-1145
dc.identifier.urihttp://hdl.handle.net/11449/34159
dc.identifier.wosWOS:000248719300017
dc.language.isoeng
dc.publisherElsevier B.V.
dc.relation.ispartofJournal of Molecular Biology
dc.relation.ispartofjcr4.894
dc.relation.ispartofsjr3,393
dc.rights.accessRightsAcesso restrito
dc.sourceWeb of Science
dc.subjectnematode anticoagulant proteinspt
dc.subjectfactor X/Xapt
dc.subjectixolarispt
dc.subjecttissue factor pathway inhibitorpt
dc.subjectactive and exo-site bindingpt
dc.titleActive and exo-site inhibition of human factor Xa: Structure of des-Gla factor Xa inhibited by NAP5, a potent nematode anticoagulant protein from Ancylostoma caninumen
dc.typeArtigo
dcterms.licensehttp://www.elsevier.com/about/open-access/open-access-policies/article-posting-policy
dcterms.rightsHolderElsevier B.V.
unesp.author.lattes9162508978945887[4]
unesp.author.orcid0000-0003-2460-1145[4]
unesp.campusUniversidade Estadual Paulista (Unesp), Instituto de Biociências Letras e Ciências Exatas, São José do Rio Pretopt

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