Effects of Chirality at Tyr13 on the Structure−Activity Relationships of ω-Conotoxins from Conus magus†
journal contributionposted on 05.05.1999 by Katherine J. Nielsen, Denise A. Adams, Paul F. Alewood, Richard J. Lewis, Linda Thomas, Tina Schroeder, David J. Craik
Any type of content formally published in an academic journal, usually following a peer-review process.
The effects of chirality inversions of Tyr13 on the structure−activity relationships of ω-conotoxins MVIIA and MVIIC were examined using a combination of 2D 1H NMR spectroscopy and radioligand binding studies specific for N-type ([125I]GVIA) and P/Q-type ([125I]MVIIC) voltage-sensitive calcium channels (VSCCs). A comparison of the Hα secondary shifts suggests that the structural scaffolds of MVIIA and MVIIC are little altered by the l- to d- inversion of Tyr13; however, the conformations of several residues in loop 2 (residues 9−14) are significantly altered. The experimentally determined 3D structure of [d-Y13]MVIIA indicates that the positions of key residues in this loop which are involved in the binding of MVIIA to the N-type VSCC (Tyr13, Arg10, and Leu11) are so changed as to render the peptide unrecognizable by its cognate ion channel. The large reduction in potency observed for MVIIA and MVIIC at both N-type and P/Q-type VSCCs is likely to stem from the change in conformation and orientation of loop 2.