Structures of heparin-derived disaccharide bound to cobra cardiotoxins: context-dependent conformational change of heparin upon binding to the rigid core of the three-fingered toxin: Biochemistry

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TypeArticle
Journal titleBiochemistry
Volume40
Issue35
Pages1043610446; # of pages: 11
SubjectACID; analysis; Animals; binding; Binding Sites; BINDING-SITE; Canada; carbohydrate; Carbohydrate Conformation; CHAIN; chemistry; Cobra; conformation; CONFORMATIONAL; CORE REGION; Direct Lytic Factors; DISACCHARIDE; disulfide; exchange; Glucosamine; Glycosaminoglycan; Glycosaminoglycans; Heparin; HIGH-RESOLUTION; interaction; Magnetic Resonance Spectroscopy; matrix; MATRIX ANALYSIS; membrane; Membranes; MODEL; MOLECULE; NMR; NOE; POLYSACCHARIDE; Polysaccharides; POTENTIAL; protein; Protein Binding; Protein Conformation; REGION; RELAXATION; RING; Role; SITE; SPECIFICITY; STATE; structure; Support,Non-U.S.Gov't; surface; TARGET
AbstractGlycosaminoglycans (GAGs) have been suggested to be a potential target for cobra cardiotoxin (CTX) with high affinity and specificity via a cationic belt at the concave surface of the polypeptide. The interaction of GAGs, such as high-molecular weight heparin, with CTXs not only can induce aggregation of CTX molecules but also can enhance their penetration into membranes. The binding of short chain heparin, such as a heparin-derived disaccharide [DeltaUA2S(1-->4)-alpha-D-GlcNS6S], to CTX A3 from Taiwan cobra (Naja atra), however, will not induce aggregation and was, therefore, investigated by high-resolution (1)H NMR. A novel heparin binding site on the convex side of the CTX, near the rigid disulfide bond-tightened core region of Cys38, was identified due to the observation of intermolecular NOEs between the protein and carbohydrate. The derived carbohydrate conformation using complete relaxation and conformational exchange matrix analysis (CORCEMA) of NOEs indicated that the glycosidic linkage conformation and the ring conformation of the unsaturated uronic acid in the bound state depended significantly on the charge context of CTX molecules near the binding site. Specifically, comparative binding studies of several heparin disaccharide homologues with two CTX homologues (CTX Tgamma from Naja nigricollis and CTX A3) indicated that the electrostatic interaction of N-sulfate of glucosamine with NH(3)(+)zeta of Lys12 and of the 2-O-sulfate of the unsaturated uronic acid with NH(3)(+)zeta of Lys5 played an important role. These results also suggest a model on how the CTX-heparin interaction may regulate heparin-induced aggregation of the toxin via the second heparin binding site
Publication date
LanguageEnglish
AffiliationNRC Institute for Biological Sciences; National Research Council Canada
Peer reviewedNo
NRC numberSUE2001A
NPARC number9371050
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Record identifier1248539f-705c-40ff-9ee6-26cf0f633dda
Record created2009-07-10
Record modified2016-05-09
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