The Experts below are selected from a list of 81 Experts worldwide ranked by ideXlab platform
Kazuki Sato - One of the best experts on this subject based on the ideXlab platform.
-
three dimensional structure in solution of the calcium channel blocker Omega Conotoxin MVIIA
Biochemistry, 1995Co-Authors: Toshiyuki Kohno, Kuniko Kobayashi, Yoshio Kodera, Tadakazu Maeda, Kazuki SatoAbstract:: The three-dimensional solution structure of Omega-Conotoxin MVIIA, a 25-mer peptide antagonist of N-type calcium channels, was determined by two-dimensional 1H NMR spectroscopy with simulated annealing calculations. A total of 13 converged structures of Omega-Conotoxin MVIIA were obtained on the basis of 273 experimental constraints, including 232 distance constraints obtained from nuclear Overhauser effect (NOE) connectivities, 22 torsion angle (phi, chi 1) constraints, and 19 constraints associated with hydrogen bonds and disulfide bonds. The atomic root mean square difference about the averaged coordinate positions is 0.47 +/- 0.08 A for the backbone atoms (N, C alpha, C) and 1.27 +/- 0.14 A for all heavy atoms of the entire peptide. The molecular structure of Omega-Conotoxin MVIIA is composed of a short triple-stranded antiparallel beta-sheet. The overall beta-sheet topology is +2x, -1, which is the same as that reported for Omega-Conotoxin GVIA, another N-type calcium channel blocker. The orientation of beta-stranded structure is similar to each other, suggesting that the conserved disulfide bond combination is essential for the molecular folding. We have recently determined by using alanine substitution analyses that Tyr 13 is essential for the activity of both toxins. On the basis of functional and structural analysis, it is shown that both Omega-Conotoxin MVIIA and GVIA retain a similar conformation to locate Tyr 13 in the appropriate position to allow binding to N-type calcium channels. These results provide a molecular basis for understanding the mechanism of calcium channel modulation through the toxin-channel interaction and insight into the discrimination of different subtypes of calcium channels.
-
tyr13 is essential for the activity of Omega Conotoxin MVIIA and gvia specific n type calcium channel blockers
Biochemical and Biophysical Research Communications, 1995Co-Authors: Jae Il Kim, M Takahashi, Atsuko Ohtake, A Wakamiya, Kazuki SatoAbstract:Abstract Two analogs of ω-Conotoxin MVIIA, a 25mer peptide neurotoxin, were synthesized by replacing Lys2 or Tyr13 with Ala. The activities of synthetic analogs were estimated from the inhibitory action on 125I-ω-Conotoxin GVIA binding to chick brain synaptic plasma membranes. As in the case of ω-Conotoxin GVIA, replacement of Tyr13 resulted in an enormous reduction in activity. In contrast, substitution of Ala for Lys2 gave only a small effect. These results indicate that Tyr13 is a critical amino acid of ω-Conotoxin MVIIA and GVIA for blocking N-type calcium channel function.
David Christopher Horwell - One of the best experts on this subject based on the ideXlab platform.
-
design and biological evaluation of non peptide analogues of Omega Conotoxin MVIIA
Bioorganic & Medicinal Chemistry Letters, 2000Co-Authors: Stefan Menzler, N Sumanchauhan, Jacob A Bikker, David Christopher HorwellAbstract:Abstract Omega-Conotoxin MVIIA, a highly potent antagonist of the N-type voltage sensitive calcium channel, has shown utility in several models of pain and ischemia. We report a series of three alkylphenyl ether based analogues which mimic three key amino acids of the toxin. Two of the compounds have been found to exhibit IC50 values of 2.7 and 3.3 μM at the human N-type voltage sensitive calcium channel.
-
synthesis of a non peptide analogue of Omega Conotoxin MVIIA
Tetrahedron Letters, 1998Co-Authors: Stefan Menzler, Jacob A Bikker, David Christopher HorwellAbstract:Abstract An efficient synthesis of an alkylphenyl ether based peptidomimetic is described. The compound mimics three key amino acids of Omega-Conotoxin MVIIA from the cone shell Conus magus and may provide an entry to the design of low molecular weight antagonists of N-type neuronal calcium channels.
Jeanfrancois Lefevre - One of the best experts on this subject based on the ideXlab platform.
-
structural and dynamic characterization of Omega Conotoxin MVIIA the binding loop exhibits slow conformational exchange
Biochemistry, 2000Co-Authors: R A Atkinson, Bruno Kieffer, Annick Dejaegere, Finton Sirockin, Jeanfrancois LefevreAbstract:Omega-Conotoxin MVIIA is a 25-residue, disulfide-bridged polypeptide from the venom of the sea snail Conus magus that binds to neuronal N-type calcium channels. It forms a compact folded structure, presenting a loop between Cys8 and Cys15 that contains a set of residues critical for its binding. The loop does not have a unique defined structure, nor is it intrinsically flexible. Broadening of a subset of resonances in the NMR spectrum at low temperature, anomalous temperature dependence of the chemical shifts of some resonances, and exchange contributions to J(0) from (13)C relaxation measurements reveal that conformational exchange affects the residues in this loop. The effects of this exchange on the calculated structure of Omega-Conotoxin MVIIA are discussed. The exchange appears to be associated with a change in the conformation of the disulfide bridge Cys8-Cys20. The implications for the use of the Omega-Conotoxins as a scaffold for carrying other functions is discussed.
-
structural and dynamic characterization of Omega Conotoxin MVIIA the binding loop exhibits slow conformational exchange
Biochemistry, 2000Co-Authors: R A Atkinson, Bruno Kieffer, Annick Dejaegere, Finton Sirockin, Jeanfrancois LefevreAbstract:ω-Conotoxin MVIIA is a 25-residue, disulfide-bridged polypeptide from the venom of the sea snail Conus magus that binds to neuronal N-type calcium channels. It forms a compact folded structure, presenting a loop between Cys8 and Cys15 that contains a set of residues critical for its binding. The loop does not have a unique defined structure, nor is it intrinsically flexible. Broadening of a subset of resonances in the NMR spectrum at low temperature, anomalous temperature dependence of the chemical shifts of some resonances, and exchange contributions to J(0) from 13C relaxation measurements reveal that conformational exchange affects the residues in this loop. The effects of this exchange on the calculated structure of ω-Conotoxin MVIIA are discussed. The exchange appears to be associated with a change in the conformation of the disulfide bridge Cys8-Cys20. The implications for the use of the ω-Conotoxins as a scaffold for carrying other functions is discussed.
Stefan Menzler - One of the best experts on this subject based on the ideXlab platform.
-
design and biological evaluation of non peptide analogues of Omega Conotoxin MVIIA
Bioorganic & Medicinal Chemistry Letters, 2000Co-Authors: Stefan Menzler, N Sumanchauhan, Jacob A Bikker, David Christopher HorwellAbstract:Abstract Omega-Conotoxin MVIIA, a highly potent antagonist of the N-type voltage sensitive calcium channel, has shown utility in several models of pain and ischemia. We report a series of three alkylphenyl ether based analogues which mimic three key amino acids of the toxin. Two of the compounds have been found to exhibit IC50 values of 2.7 and 3.3 μM at the human N-type voltage sensitive calcium channel.
-
synthesis of a non peptide analogue of Omega Conotoxin MVIIA
Tetrahedron Letters, 1998Co-Authors: Stefan Menzler, Jacob A Bikker, David Christopher HorwellAbstract:Abstract An efficient synthesis of an alkylphenyl ether based peptidomimetic is described. The compound mimics three key amino acids of Omega-Conotoxin MVIIA from the cone shell Conus magus and may provide an entry to the design of low molecular weight antagonists of N-type neuronal calcium channels.
R A Atkinson - One of the best experts on this subject based on the ideXlab platform.
-
structural and dynamic characterization of Omega Conotoxin MVIIA the binding loop exhibits slow conformational exchange
Biochemistry, 2000Co-Authors: R A Atkinson, Bruno Kieffer, Annick Dejaegere, Finton Sirockin, Jeanfrancois LefevreAbstract:Omega-Conotoxin MVIIA is a 25-residue, disulfide-bridged polypeptide from the venom of the sea snail Conus magus that binds to neuronal N-type calcium channels. It forms a compact folded structure, presenting a loop between Cys8 and Cys15 that contains a set of residues critical for its binding. The loop does not have a unique defined structure, nor is it intrinsically flexible. Broadening of a subset of resonances in the NMR spectrum at low temperature, anomalous temperature dependence of the chemical shifts of some resonances, and exchange contributions to J(0) from (13)C relaxation measurements reveal that conformational exchange affects the residues in this loop. The effects of this exchange on the calculated structure of Omega-Conotoxin MVIIA are discussed. The exchange appears to be associated with a change in the conformation of the disulfide bridge Cys8-Cys20. The implications for the use of the Omega-Conotoxins as a scaffold for carrying other functions is discussed.
-
structural and dynamic characterization of Omega Conotoxin MVIIA the binding loop exhibits slow conformational exchange
Biochemistry, 2000Co-Authors: R A Atkinson, Bruno Kieffer, Annick Dejaegere, Finton Sirockin, Jeanfrancois LefevreAbstract:ω-Conotoxin MVIIA is a 25-residue, disulfide-bridged polypeptide from the venom of the sea snail Conus magus that binds to neuronal N-type calcium channels. It forms a compact folded structure, presenting a loop between Cys8 and Cys15 that contains a set of residues critical for its binding. The loop does not have a unique defined structure, nor is it intrinsically flexible. Broadening of a subset of resonances in the NMR spectrum at low temperature, anomalous temperature dependence of the chemical shifts of some resonances, and exchange contributions to J(0) from 13C relaxation measurements reveal that conformational exchange affects the residues in this loop. The effects of this exchange on the calculated structure of ω-Conotoxin MVIIA are discussed. The exchange appears to be associated with a change in the conformation of the disulfide bridge Cys8-Cys20. The implications for the use of the ω-Conotoxins as a scaffold for carrying other functions is discussed.
