Intermolecular interactions and characterization of the novel factor Xa exosite involved in macromolecular recognition and inhibition: Crystal structure of human Gla-domainless factor Xa complexed with the anticoagulant protein NAPc2 from the hematophagous nematode Ancylostoma caninum
Contribuinte(s) |
Universidade Estadual Paulista (UNESP) |
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Data(s) |
20/05/2014
20/05/2014
16/02/2007
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Resumo |
NAPc2, an anticoagulant protein from the hematophagous nematode Ancylostoma caninum evaluated in phase-II/IIa clinical trials, inhibits the extrinsic blood coagulation pathway by a two step mechanism, initially interacting with the hitherto uncharacterized factor Xa exosite involved in macromolecular recognition and subsequently inhibiting factor VIIa (K-i = 8.4 pM) of the factor VIIa/tissue factor complex. NAPc2 is highly flexible, becoming partially ordered and undergoing significant structural changes in the C terminus upon binding to the factor Xa exosite. In the crystal structure of the ternary factor Xa/NAPc2/selectide complex, the binding interface consists of an intermolecular antiparallel beta-sheet formed by the segment of the polypeptide chain consisting of residues 74-80 of NAPc2 with the residues 86-93 of factor Xa that is additional maintained by contacts between the short helical segment (residues 67-73) and a turn (residues 26-29) of NAPc2 with the short C-terminal helix of factor Xa (residues 233-243). This exosite is physiologically highly relevant for the recognition and inhibition of factor X/Xa by macromolecular substrates and provides a structural motif for the development of a new class of inhibitors for the treatment of deep vein thrombosis and angioplasty. (c) 2006 Elsevier Ltd. All rights reserved. |
Formato |
602-610 |
Identificador |
http://dx.doi.org/10.1016/j.jmb.2006.11.040 Journal of Molecular Biology. London: Academic Press Ltd Elsevier B.V. Ltd, v. 366, n. 2, p. 602-610, 2007. 0022-2836 http://hdl.handle.net/11449/21975 10.1016/j.jmb.2006.11.040 WOS:000244184100022 |
Idioma(s) |
eng |
Publicador |
Elsevier B.V. |
Relação |
Journal of Molecular Biology |
Direitos |
closedAccess |
Palavras-Chave | #factor Xa exosite #nematode anticoagulant protein #selectide inhibitor #factor VIIa/tissue factor complex #inhibition |
Tipo |
info:eu-repo/semantics/article |