'''NMR STRUCTURE OF AN ENGINEERED CONTRYPHAN CYCLIC PEPTIDE (MOTIF CPXXPXC)'''
===NMR STRUCTURE OF AN ENGINEERED CONTRYPHAN CYCLIC PEPTIDE (MOTIF CPXXPXC)===
==Overview==
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Contryphan-R, from venom of the cone-shell Conus radiatus, represents a novel cyclic peptide scaffold onto which residues may be grafted to mimic unrelated protein surfaces. Three substitutions were made at the x and X positions of the disulfide-bridged motif CPxXPXC, where X and x represent any L- and D-handed residues, respectively, P represents proline or hydroxyproline, and C a half-cystine. These substitutions were designed to mimic part of the pharmacophore of the unrelated globular polypeptide omega-conotoxin GVIA, which blocks N-type calcium channels. The structure of this engineered contryphan, YNK-contryphan-R ([D-Tyr4, Asn5, Lys7]contryphan-R), is shown to be similar to that of native contryphan-R (Pallaghy et al., Biochemistry, 1999, Vol. 38, pp. 13553-13559), confirming that the scaffold is robust with respect to the multiple substitutions. In particular, the alpha-beta bond vectors characterising the orientation of the side chains relative to the backbone are similar in contryphan-R, YNK-contryphan-R, and omega-conotoxin GVIA, which is the required result for a scaffold-based approach to molecular design. The solution structure of YNK-contryphan-R has an N-terminal, nonhydrogen-bonded, chain reversal centered on Hyp3-D-Trp4, and a C-terminal type I beta-turn. A minor form due to cis-trans isomerism of the Hyp2-Cys3 peptide bond is present in YNK-contryphan-R in a larger proportion than in contryphan-R. It is evident, particularly from the (3)J(HalphaHN) coupling constants, that YNK-contryphan-R is more flexible than contryphan-R, probably due to the absence in YNK-contryphan-R of the Pro-Trp packing present in the native molecule. Nevertheless, the structure confirms that cyclic peptide molecular designs can achieve the intended conformations.
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==About this Structure==
==About this Structure==
Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1D7T OCA].
Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1D7T OCA].
==Reference==
==Reference==
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[[Category: D-handed]]
[[Category: D-handed]]
[[Category: Disulfide bond]]
[[Category: Disulfide bond]]
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Revision as of 19:38, 30 June 2008
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