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| - | [[Image:1ttk.gif|left|200px]]<br /><applet load="1ttk" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1ttk" /> | |
| - | '''NMR solution structure of omega-conotoxin MVIIA, a N-type calcium channel blocker'''<br /> | |
| | | | |
| - | ==Overview== | + | ==NMR solution structure of omega-conotoxin MVIIA, a N-type calcium channel blocker== |
| - | Neurotransmitter release from preganglionic parasympathetic neurons is, resistant to inhibition by selective antagonists of L-, N-, P/Q-, R-, and, T-type calcium channels. In this study, the effects of different, omega-conotoxins from genus Conus were investigated on current, flow-through cloned voltage-sensitive calcium channels expressed in, Xenopus oocytes and nerve-evoked transmitter release from the intact, preganglionic cholinergic nerves innervating the rat submandibular, ganglia. Our results indicate that omega-conotoxin CVID from Conus catus, inhibits a pharmacologically distinct voltage-sensitive calcium channel, involved in neurotransmitter release, whereas omega-conotoxin MVIIA had no, effect. omega-Conotoxin CVID and MVIIA inhibited depolarization-activated, Ba(2+) currents recorded from oocytes expressing N-type but not L- or, R-type calcium channels. High affinity inhibition of the CVID-sensitive, calcium channel was enhanced when position 10 of the omega-conotoxin was, occupied by the smaller residue lysine as found in CVID instead of an, arginine as found in MVIIA. Given that relatively small differences in the, sequence of the N-type calcium channel alpha(1B) subunit can influence, omega-conotoxin access (Feng, Z. P., Hamid, J., Doering, C., Bosey, G. M., Snutch, T. P., and Zamponi, G. W. (2001) J. Biol. Chem. 276, 15728-15735), it is likely that the calcium channel in preganglionic nerve terminals, targeted by CVID is a N-type (Ca(v)2.2) calcium channel variant. | + | <StructureSection load='1ttk' size='340' side='right'caption='[[1ttk]]' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1ttk]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Conus_magus Conus magus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TTK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1TTK FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 17 models</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr> |
| | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1ttk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ttk OCA], [https://pdbe.org/1ttk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ttk RCSB], [https://www.ebi.ac.uk/pdbsum/1ttk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ttk ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/O17A_CONMA O17A_CONMA] Omega-conotoxins act at presynaptic membranes, they bind and block voltage-gated calcium channels. This toxin blocks Cav2.2/CACNA1B calcium channels (IC(50)=0.67-208 nM) (PubMed:26344359, PubMed:34589389, PubMed:7826361). It acts by neutralizing the outer electronegativity and sterically hindering the ion access path to the entrance of the channel selectivity filter (PubMed:34234349). It also shows antiproliferative effects on different glioma cell lines (M059J, U-138MG and U-251MG) (PubMed:28202361). In vivo, is lethal to fish (PubMed:26344359, PubMed:34589389). In vivo, injection into mammals induces adverse effects, such as tremor, diminution of spontaneous locomotor activity and bad coordinated locomotion (PubMed:26344359). In addition, it causes reduction of tumor area in the mouse glioma model, that is induced by the orthotopic injection of GL261 cells into the brain (PubMed:28202361).<ref>PMID:26344359</ref> <ref>PMID:34234349</ref> <ref>PMID:7826361</ref> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Neurotransmitter release from preganglionic parasympathetic neurons is resistant to inhibition by selective antagonists of L-, N-, P/Q-, R-, and T-type calcium channels. In this study, the effects of different omega-conotoxins from genus Conus were investigated on current flow-through cloned voltage-sensitive calcium channels expressed in Xenopus oocytes and nerve-evoked transmitter release from the intact preganglionic cholinergic nerves innervating the rat submandibular ganglia. Our results indicate that omega-conotoxin CVID from Conus catus inhibits a pharmacologically distinct voltage-sensitive calcium channel involved in neurotransmitter release, whereas omega-conotoxin MVIIA had no effect. omega-Conotoxin CVID and MVIIA inhibited depolarization-activated Ba(2+) currents recorded from oocytes expressing N-type but not L- or R-type calcium channels. High affinity inhibition of the CVID-sensitive calcium channel was enhanced when position 10 of the omega-conotoxin was occupied by the smaller residue lysine as found in CVID instead of an arginine as found in MVIIA. Given that relatively small differences in the sequence of the N-type calcium channel alpha(1B) subunit can influence omega-conotoxin access (Feng, Z. P., Hamid, J., Doering, C., Bosey, G. M., Snutch, T. P., and Zamponi, G. W. (2001) J. Biol. Chem. 276, 15728-15735), it is likely that the calcium channel in preganglionic nerve terminals targeted by CVID is a N-type (Ca(v)2.2) calcium channel variant. |
| | | | |
| - | ==About this Structure==
| + | Omega-conotoxin CVID inhibits a pharmacologically distinct voltage-sensitive calcium channel associated with transmitter release from preganglionic nerve terminals.,Adams DJ, Smith AB, Schroeder CI, Yasuda T, Lewis RJ J Biol Chem. 2003 Feb 7;278(6):4057-62. Epub 2002 Nov 18. PMID:12441339<ref>PMID:12441339</ref> |
| - | 1TTK is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ] with NH2 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1TTK OCA].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | Omega-conotoxin CVID inhibits a pharmacologically distinct voltage-sensitive calcium channel associated with transmitter release from preganglionic nerve terminals., Adams DJ, Smith AB, Schroeder CI, Yasuda T, Lewis RJ, J Biol Chem. 2003 Feb 7;278(6):4057-62. Epub 2002 Nov 18. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12441339 12441339]
| + | </div> |
| - | [[Category: Single protein]]
| + | <div class="pdbe-citations 1ttk" style="background-color:#fffaf0;"></div> |
| - | [[Category: Adams, D.J.]]
| + | == References == |
| - | [[Category: Lewis, R.J.]]
| + | <references/> |
| - | [[Category: Schroeder, C.I.]] | + | __TOC__ |
| - | [[Category: Smith, A.B.]] | + | </StructureSection> |
| - | [[Category: Yasuda, T.]] | + | [[Category: Conus magus]] |
| - | [[Category: NH2]] | + | [[Category: Large Structures]] |
| - | [[Category: amidated c-terminal]] | + | [[Category: Adams DJ]] |
| - | [[Category: disulfide rich]] | + | [[Category: Lewis RJ]] |
| - | [[Category: four loop frame work]] | + | [[Category: Schroeder CI]] |
| - | | + | [[Category: Smith AB]] |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 03:34:56 2007''
| + | [[Category: Yasuda T]] |
| Structural highlights
Function
O17A_CONMA Omega-conotoxins act at presynaptic membranes, they bind and block voltage-gated calcium channels. This toxin blocks Cav2.2/CACNA1B calcium channels (IC(50)=0.67-208 nM) (PubMed:26344359, PubMed:34589389, PubMed:7826361). It acts by neutralizing the outer electronegativity and sterically hindering the ion access path to the entrance of the channel selectivity filter (PubMed:34234349). It also shows antiproliferative effects on different glioma cell lines (M059J, U-138MG and U-251MG) (PubMed:28202361). In vivo, is lethal to fish (PubMed:26344359, PubMed:34589389). In vivo, injection into mammals induces adverse effects, such as tremor, diminution of spontaneous locomotor activity and bad coordinated locomotion (PubMed:26344359). In addition, it causes reduction of tumor area in the mouse glioma model, that is induced by the orthotopic injection of GL261 cells into the brain (PubMed:28202361).[1] [2] [3]
Publication Abstract from PubMed
Neurotransmitter release from preganglionic parasympathetic neurons is resistant to inhibition by selective antagonists of L-, N-, P/Q-, R-, and T-type calcium channels. In this study, the effects of different omega-conotoxins from genus Conus were investigated on current flow-through cloned voltage-sensitive calcium channels expressed in Xenopus oocytes and nerve-evoked transmitter release from the intact preganglionic cholinergic nerves innervating the rat submandibular ganglia. Our results indicate that omega-conotoxin CVID from Conus catus inhibits a pharmacologically distinct voltage-sensitive calcium channel involved in neurotransmitter release, whereas omega-conotoxin MVIIA had no effect. omega-Conotoxin CVID and MVIIA inhibited depolarization-activated Ba(2+) currents recorded from oocytes expressing N-type but not L- or R-type calcium channels. High affinity inhibition of the CVID-sensitive calcium channel was enhanced when position 10 of the omega-conotoxin was occupied by the smaller residue lysine as found in CVID instead of an arginine as found in MVIIA. Given that relatively small differences in the sequence of the N-type calcium channel alpha(1B) subunit can influence omega-conotoxin access (Feng, Z. P., Hamid, J., Doering, C., Bosey, G. M., Snutch, T. P., and Zamponi, G. W. (2001) J. Biol. Chem. 276, 15728-15735), it is likely that the calcium channel in preganglionic nerve terminals targeted by CVID is a N-type (Ca(v)2.2) calcium channel variant.
Omega-conotoxin CVID inhibits a pharmacologically distinct voltage-sensitive calcium channel associated with transmitter release from preganglionic nerve terminals.,Adams DJ, Smith AB, Schroeder CI, Yasuda T, Lewis RJ J Biol Chem. 2003 Feb 7;278(6):4057-62. Epub 2002 Nov 18. PMID:12441339[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wang F, Yan Z, Liu Z, Wang S, Wu Q, Yu S, Ding J, Dai Q. Molecular basis of toxicity of N-type calcium channel inhibitor MVIIA. Neuropharmacology. 2016 Feb;101:137-45. PMID:26344359 doi:10.1016/j.neuropharm.2015.08.047
- ↑ Gao S, Yao X, Yan N. Structure of human Ca(v)2.2 channel blocked by the painkiller ziconotide. Nature. 2021 Aug;596(7870):143-147. PMID:34234349 doi:10.1038/s41586-021-03699-6
- ↑ Kim JI, Takahashi M, Ohtake A, Wakamiya A, Sato K. Tyr13 is essential for the activity of omega-conotoxin MVIIA and GVIA, specific N-type calcium channel blockers. Biochem Biophys Res Commun. 1995 Jan 17;206(2):449-54. PMID:7826361 doi:10.1006/bbrc.1995.1063
- ↑ Adams DJ, Smith AB, Schroeder CI, Yasuda T, Lewis RJ. Omega-conotoxin CVID inhibits a pharmacologically distinct voltage-sensitive calcium channel associated with transmitter release from preganglionic nerve terminals. J Biol Chem. 2003 Feb 7;278(6):4057-62. Epub 2002 Nov 18. PMID:12441339 doi:http://dx.doi.org/10.1074/jbc.M209969200
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