title: Effects of chirality at Tyr13 on the structure-activity relationships of omega-conotoxins from Conus magus.
abstract: The effects of chirality inversions of Tyr13 on the structure-activity relationships of omega-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 Halpha 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.
authors.affiliation: Centre for Drug Design and Development, The University of Queensland, Brisbane.
authors.forename: K J
authors.initials: KJ
authors.lastname: Nielsen
authors.forename: D A
authors.initials: DA
authors.lastname: Adams
authors.forename: P F
authors.initials: PF
authors.lastname: Alewood
authors.forename: R J
authors.initials: RJ
authors.lastname: Lewis
authors.forename: L
authors.initials: L
authors.lastname: Thomas
authors.forename: T
authors.initials: T
authors.lastname: Schroeder
authors.forename: D J
authors.initials: DJ
authors.lastname: Craik
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008978:Mollusk Venoms / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D020033:Protein Isoforms / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D011522:Protons; D011869:Radioligand Assay; D051381:Rats; D012908:Snails; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000737:chemistry*; D020960:omega-Conotoxins
chemical_list: D008978:Mollusk Venoms; D010455:Peptides; D020033:Protein Isoforms; D011522:Protons; D020960:omega-Conotoxins; C075851:omega-conotoxin-MVIIC; D014443:Tyrosine; C078452:ziconotide