1ro3
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New structural insights on short disintegrin echistatin by NMR
OverviewOverview
Echistatin is a potent antagonist of the integrins alpha(v)beta3, alpha5beta1 and alpha(IIb)beta3. Its full inhibitory activity depends on, an RGD (Arg-Gly-Asp) motif expressed at the tip of the integrin-binding, loop and on its C-terminal tail. Previous NMR structures of echistatin, showed a poorly defined integrin-recognition sequence and an incomplete, C-terminal tail, which left the molecular basis of the functional synergy, between the RGD loop and the C-terminal region unresolved. We report a, high-resolution structure of echistatin and an analysis of its internal, motions by off-resonance ROESY (rotating-frame Overhauser enhancement, spectroscopy). The full-length C-terminal polypeptide is visible as a, beta-hairpin running parallel to the RGD loop and exposing at the tip, residues Pro43, His44 and Lys45. The side chains of the amino acids of the, RGD motif have well-defined conformations. The integrin-binding loop, displays an overall movement with maximal amplitude of 30 degrees ., Internal angular motions in the 100-300 ps timescale indicate increased, flexibility for the backbone atoms at the base of the integrin-recognition, loop. In addition, backbone atoms of the amino acids Ala23 (flanking the, R24GD26 tripeptide) and Asp26 of the integrin-binding motif showed, increased angular mobility, suggesting the existence of major and minor, hinge effects at the base and the tip, respectively, of the RGD loop. A, strong network of NOEs (nuclear Overhauser effects) between residues of, the RGD loop and the C-terminal tail indicate concerted motions between, these two functional regions. A full-length echistatin-alpha(v)beta3, docking model suggests that echistatin's C-terminal amino acids may, contact alpha(v)-subunit residues and provides new insights to delineate, structure-function correlations.
About this StructureAbout this Structure
1RO3 is a Single protein structure of sequence from Echis carinatus. Full crystallographic information is available from OCA.
ReferenceReference
Conformation and concerted dynamics of the integrin-binding site and the C-terminal region of echistatin revealed by homonuclear NMR., Monleon D, Esteve V, Kovacs H, Calvete JJ, Celda B, Biochem J. 2005 Apr 1;387(Pt 1):57-66. PMID:15535803
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