Effects of chirality at Tyr13 on the structure-activity relationships of omega-conotoxins from Conus magus

The effects of chirality inversions of Tyr13 on the structure-activity rela tionships of omega-conotoxins MVIIA and MVIIC were examined using a combina tion of 2D H-1 NMR spectroscopy and radioligand binding studies specific fo r N-type ([I-125]GVIA) and P/Q-type ([I-125]MVIIC) voltage-sensitive calciu m channels (VSCCs). A comparison of the H alpha secondary shifts suggests t hat 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 det ermined 3D structure of [D-Y13]MVIIA indicates that the positions of key re sidues in this loop which are involved in the binding of MVIIA to the N-typ e VSCC (Tyr13, Arg10, and Leu11) are so changed as to render the peptide un recognizable by its cognate ion channel. The large reduction in potency obs erved for MVIIA and MVIIC at both N-type and P/Q-type VSCCs is likely to st em from the change in conformation and orientation of loop 2.