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1rmk

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Solution structure of conotoxin MrVIB

Structural highlights

1rmk is a 1 chain structure with sequence from Conus marmoreus. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

O16B_CONMR MuO-conotoxins are gating-modifier toxins that inhibit sodium current by trapping the domain II voltage sensor in the closed position to prevent opening of the sodium channel. This toxin has a preference for Nav1.4/SCN4A over Nav1.2/SCN2A sodium channels. It blocks Nav channels by interacting mainly with the C-terminal part of the pore loop of domain-3. It also blocks fast-inactivating calcium current. Blocks Nav1.8/SCN10A sodium channels and has potent and long-lasting local anesthetic effects. It can also block propagation of action potentials in A- and C-fibers in sciatic nerve as well as skeletal muscle in isolated preparations.^[1] ^[2]

Publication Abstract from PubMed

The microO-conotoxins are an intriguing class of conotoxins targeting various voltage-dependent sodium channels and molluscan calcium channels. In the current study, we have shown MrVIA and MrVIB to be the first known peptidic inhibitors of the transient tetrodotoxin-resistant (TTX-R) Na(+) current in rat dorsal root ganglion neurons, in addition to inhibiting tetrodotoxin-sensitive Na(+) currents. Human TTX-R sodium channels are a therapeutic target for indications such as pain, highlighting the importance of the microO-conotoxins as potential leads for drug development. Furthermore, we have used NMR spectroscopy to provide the first structural information on this class of conotoxins. MrVIA and MrVIB are hydrophobic peptides that aggregate in aqueous solution but were solubilized in 50% acetonitrile/water. The three-dimensional structure of MrVIB consists of a small beta-sheet and a cystine knot arrangement of the three-disulfide bonds. It contains four backbone "loops" between successive cysteine residues that are exposed to the solvent to varying degrees. The largest of these, loop 2, is the most disordered part of the molecule, most likely due to flexibility in solution. This disorder is the most striking difference between the structures of MrVIB and the known delta- and omega-conotoxins, which along with the microO-conotoxins are members of the O superfamily. Loop 2 of omega-conotoxins has previously been shown to contain residues critical for binding to voltage-gated calcium channels, and it is interesting to speculate that the flexibility observed in MrVIB may accommodate binding to both sodium and molluscan calcium channels.

Structures of muO-conotoxins from Conus marmoreus. I nhibitors of tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels in mammalian sensory neurons.,Daly NL, Ekberg JA, Thomas L, Adams DJ, Lewis RJ, Craik DJ J Biol Chem. 2004 Jun 11;279(24):25774-82. Epub 2004 Mar 24. PMID:15044438^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Zorn S, Leipold E, Hansel A, Bulaj G, Olivera BM, Terlau H, Heinemann SH. The muO-conotoxin MrVIA inhibits voltage-gated sodium channels by associating with domain-3. FEBS Lett. 2006 Feb 20;580(5):1360-4. Epub 2006 Jan 26. PMID:16458302 doi:http://dx.doi.org/10.1016/j.febslet.2006.01.057
↑ Bulaj G, Zhang MM, Green BR, Fiedler B, Layer RT, Wei S, Nielsen JS, Low SJ, Klein BD, Wagstaff JD, Chicoine L, Harty TP, Terlau H, Yoshikami D, Olivera BM. Synthetic muO-conotoxin MrVIB blocks TTX-resistant sodium channel NaV1.8 and has a long-lasting analgesic activity. Biochemistry. 2006 Jun 13;45(23):7404-14. PMID:16752929 doi:http://dx.doi.org/10.1021/bi060159+
↑ Daly NL, Ekberg JA, Thomas L, Adams DJ, Lewis RJ, Craik DJ. Structures of muO-conotoxins from Conus marmoreus. I nhibitors of tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels in mammalian sensory neurons. J Biol Chem. 2004 Jun 11;279(24):25774-82. Epub 2004 Mar 24. PMID:15044438 doi:http://dx.doi.org/10.1074/jbc.M313002200

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1rmk"

@@ Line 1: / Line 1: @@
 ==Solution structure of conotoxin MrVIB==
-<StructureSection load='1rmk' size='340' side='right'caption='[[1rmk]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='1rmk' size='340' side='right'caption='[[1rmk]]' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[1rmk]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Conus_marmoreus Conus marmoreus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1RMK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1RMK FirstGlance]. <br>
-</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=1rmk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1rmk OCA], [https://pdbe.org/1rmk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1rmk RCSB], [https://www.ebi.ac.uk/pdbsum/1rmk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1rmk ProSAT]</span></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</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=1rmk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1rmk OCA], [https://pdbe.org/1rmk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1rmk RCSB], [https://www.ebi.ac.uk/pdbsum/1rmk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1rmk ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/CO16B_CONMR CO16B_CONMR]] Mu-conotoxins block voltage-gated sodium channels. Has a preference for Nav1.4/SCN4A over Nav1.2/SCN2A sodium channels. Blocks Nav channels by interacting mainly with the C-terminal part of the pore loop of domain-3. Also blocks fast-inactivating calcium current. Blocks Nav1.8/SCN10A sodium channels and has potent and long-lasting local anesthetic effects. Can also block propagation of action potentials in A- and C-fibers in sciatic nerve as well as skeletal muscle in isolated preparations.<ref>PMID:16458302</ref> <ref>PMID:16752929</ref>
+[https://www.uniprot.org/uniprot/O16B_CONMR O16B_CONMR] MuO-conotoxins are gating-modifier toxins that inhibit sodium current by trapping the domain II voltage sensor in the closed position to prevent opening of the sodium channel. This toxin has a preference for Nav1.4/SCN4A over Nav1.2/SCN2A sodium channels. It blocks Nav channels by interacting mainly with the C-terminal part of the pore loop of domain-3. It also blocks fast-inactivating calcium current. Blocks Nav1.8/SCN10A sodium channels and has potent and long-lasting local anesthetic effects. It can also block propagation of action potentials in A- and C-fibers in sciatic nerve as well as skeletal muscle in isolated preparations.<ref>PMID:16458302</ref> <ref>PMID:16752929</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 24: @@
 [[Category: Conus marmoreus]]
 [[Category: Large Structures]]
-[[Category: Adams, D J]]
+[[Category: Adams DJ]]
-[[Category: Craik, D J]]
+[[Category: Craik DJ]]
-[[Category: Daly, N L]]
+[[Category: Daly NL]]
-[[Category: Ekberg, J A]]
+[[Category: Ekberg JA]]
-[[Category: Lewis, R J]]
+[[Category: Lewis RJ]]
-[[Category: Thomas, L]]
+[[Category: Thomas L]]
-[[Category: Beta sheet]]
-[[Category: Cystine knot]]
-[[Category: Toxin]]

1rmk

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Current revision

Solution structure of conotoxin MrVIB

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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