1D7T

NMR STRUCTURE OF AN ENGINEERED CONTRYPHAN CYCLIC PEPTIDE (MOTIF CPXXPXC)

Summary for 1D7T

• Entry DOI: 10.2210/pdb1d7t/pdb
• Descriptor: YNK-CONTRYPHAN (1 entity in total)
• Functional Keywords: disulfide bond, d-handed, beta turn, cis proline, de novo protein
• Biological source: synthetic construct
• Total number of polymer chains: 1
• Total formula weight: 897.05

Authors

Pallaghy, P.K.,Norton, R.S. (deposition date: 1999-10-19, release date: 2000-09-13, Last modification date: 2025-03-26)

Primary citation

Pallaghy, P.K.,Norton, R.S.
The cyclic contryphan motif CPxXPXC, a robust scaffold potentially useful as an omega-conotoxin mimic.
Biopolymers, 54:173-179, 2000

PubMed Abstract: 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.

PubMed: 10861378
DOI: 10.1002/1097-0282(200009)54:3<173::AID-BIP30>3.3.CO;2-1

Experimental method

SOLUTION NMR