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Conformation and concerted dynamics of the integrin-binding site and the C-terminal region of echistatin revealed by homonuclear NMR
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Conformation and concerted dynamics of the integrin-binding site and the C-terminal region of echistatin revealed by homonuclear NMR
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| dc.contributor.author | Monleon Salvado, Daniel | |
| dc.contributor.author | Esteve Moya, Vicent | |
| dc.contributor.author | Calvete Chornet, Julio | |
| dc.contributor.author | Celda Muñoz, Bernardo | |
| dc.contributor.author | Kovacs, Helena | |
| dc.date.accessioned | 2010-06-29T10:35:31Z | |
| dc.date.available | 2010-06-29T10:35:31Z | |
| dc.date.issued | 2005 | |
| dc.identifier.citation | Monleon Salvado, Daniel; Esteve Moya, Vicent; Calvete Chornet, Julio; Celda Muñoz, Bernardo; Kovacs, Helena. Conformation and concerted dynamics of the integrin-binding site and the C-terminal region of echistatin revealed by homonuclear NMR. En Biochemical Journal 387, 2005, 57–66 | en |
| dc.identifier.uri | http://hdl.handle.net/10550/13994 | |
| dc.description.abstract | Echistatin is a potent antagonist of the integrins αvβ3, α5β1 and αIIbβ3. 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 fulllength C-terminal polypeptide is visible as a β-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◦. 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– αvβ3 docking model suggests that echistatin’s C-terminal amino acids may contact αv-subunit residues and provides new insights to delineate structure–function correlations. | en |
| dc.language.iso | en | en |
| dc.subject | RGD disintegrin; Echistatin; Integrin; NMR protein dynamics determination; Off-resonance rotating-frame Overhauser enhancement spectroscopy (off-resonance ROESY) | en |
| dc.title | Conformation and concerted dynamics of the integrin-binding site and the C-terminal region of echistatin revealed by homonuclear NMR | en |
| dc.type | journal article | es_ES |
| dc.subject.unesco | UNESCO::CIENCIAS DE LA VIDA::Bioquímica | en |
| dc.identifier.idgrec | 034427 | en |
| dc.type.hasVersion | VoR | es_ES |
| dc.identifier.url | http://www.biochemj.org/bj/387/0057/3870057.pdf | en |
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