1r9i

From Proteopedia

(Difference between revisions)

Current revision

NMR Solution Structure of PIIIA toxin, NMR, 20 structures

Structural highlights

1r9i is a 1 chain structure with sequence from Conus purpurascens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR, 20 models
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CM3A_CONPU Mu-conotoxins block voltage-gated sodium channels (Nav). This toxin potently blocks rNav1.4/SCN4A. It also moderately blocks rNav1.1/SCN1A, rNav1.2/SCN2A, rNav1.3/SCN3A, mNav1.6/SCN8A, and h/rNav1.7/SCN9A. This inhibition is reversible. The block of SCN1A, SCN2A, and SCN8A is modified when beta-subunits are coexpressed with alpha subunits. Hence, blocks of channels containing the beta-1 and beta-3 subunits are more potent (compared to channels without beta subunits), whereas blocks of channels containing the beta-2 and beta-4 are less potent (compared to channels without beta subunits). This peptide causes flaccid paralysis in both mice and fish.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Mu-conotoxins are peptide inhibitors of voltage-sensitive sodium channels (VSSCs). Synthetic forms of mu-conotoxins PIIIA and PIIIA-(2-22) were found to inhibit tetrodotoxin (TTX)-sensitive VSSC current but had little effect on TTX-resistant VSSC current in sensory ganglion neurons. In rat brain neurons, these peptides preferentially inhibited the persistent over the transient VSSC current. Radioligand binding assays revealed that PIIIA, PIIIA-(2-22), and mu-conotoxins GIIIB discriminated among TTX-sensitive VSSCs in rat brain, that these and GIIIC discriminated among the corresponding VSSCs in human brain, and GIIIA had low affinity for neuronal VSSCs. (1)H NMR studies found that PIIIA adopts two conformations in solution due to cis/trans isomerization at hydroxyproline 8. The major trans conformation results in a three-dimensional structure that is significantly different from the previously identified conformation of mu-conotoxins GIIIA and GIIIB that selectively target TTX-sensitive muscle VSSCs. Comparison of the structures and activity of PIIIA to muscle-selective mu-conotoxins provides an insight into the structural requirements for inhibition of different TTX-sensitive sodium channels by mu-conotoxins.

Solution structure of mu-conotoxin PIIIA, a preferential inhibitor of persistent tetrodotoxin-sensitive sodium channels.,Nielsen KJ, Watson M, Adams DJ, Hammarstrom AK, Gage PW, Hill JM, Craik DJ, Thomas L, Adams D, Alewood PF, Lewis RJ J Biol Chem. 2002 Jul 26;277(30):27247-55. Epub 2002 May 2. PMID:12006587^[6]

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

References

↑ Holford M, Zhang MM, Gowd KH, Azam L, Green BR, Watkins M, Ownby JP, Yoshikami D, Bulaj G, Olivera BM. Pruning nature: Biodiversity-derived discovery of novel sodium channel blocking conotoxins from Conus bullatus. Toxicon. 2009 Jan;53(1):90-8. doi: 10.1016/j.toxicon.2008.10.017. Epub 2008 Nov, 20. PMID:18950653 doi:http://dx.doi.org/10.1016/j.toxicon.2008.10.017
↑ Wilson MJ, Yoshikami D, Azam L, Gajewiak J, Olivera BM, Bulaj G, Zhang MM. mu-Conotoxins that differentially block sodium channels NaV1.1 through 1.8 identify those responsible for action potentials in sciatic nerve. Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10302-7. doi:, 10.1073/pnas.1107027108. Epub 2011 Jun 7. PMID:21652775 doi:http://dx.doi.org/10.1073/pnas.1107027108
↑ Favreau P, Benoit E, Hocking HG, Carlier L, D'hoedt D, Leipold E, Markgraf R, Schlumberger S, Cordova MA, Gaertner H, Paolini-Bertrand M, Hartley O, Tytgat J, Heinemann SH, Bertrand D, Boelens R, Stocklin R, Molgo J. Pharmacological characterization of a novel mu-conopeptide, CnIIIC, indicates potent and preferential inhibition of sodium channel subtypes (Na(V) 1.2/1.4) and reveals unusual activity on neuronal nicotinic acetylcholine receptors. Br J Pharmacol. 2012 Jan 9. doi: 10.1111/j.1476-5381.2012.01837.x. PMID:22229737 doi:10.1111/j.1476-5381.2012.01837.x
↑ Tietze AA, Tietze D, Ohlenschlager O, Leipold E, Ullrich F, Kuhl T, Mischo A, Buntkowsky G, Gorlach M, Heinemann SH, Imhof D. Structurally diverse mu-conotoxin PIIIA isomers block sodium channel NaV 1.4. Angew Chem Int Ed Engl. 2012 Apr 23;51(17):4058-61. doi: 10.1002/anie.201107011. , Epub 2012 Mar 12. PMID:22407516 doi:http://dx.doi.org/10.1002/anie.201107011
↑ Zhang MM, Wilson MJ, Azam L, Gajewiak J, Rivier JE, Bulaj G, Olivera BM, Yoshikami D. Co-expression of Na(V)beta subunits alters the kinetics of inhibition of voltage-gated sodium channels by pore-blocking mu-conotoxins. Br J Pharmacol. 2013 Apr;168(7):1597-610. doi: 10.1111/bph.12051. PMID:23146020 doi:http://dx.doi.org/10.1111/bph.12051
↑ Nielsen KJ, Watson M, Adams DJ, Hammarstrom AK, Gage PW, Hill JM, Craik DJ, Thomas L, Adams D, Alewood PF, Lewis RJ. Solution structure of mu-conotoxin PIIIA, a preferential inhibitor of persistent tetrodotoxin-sensitive sodium channels. J Biol Chem. 2002 Jul 26;277(30):27247-55. Epub 2002 May 2. PMID:12006587 doi:10.1074/jbc.M201611200

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/1r9i"

@@ Line 1: / Line 1: @@
-{{Seed}}
-[[Image:1r9i.png|left|200px]]
-<!--
+==NMR Solution Structure of PIIIA toxin, NMR, 20 structures==
-The line below this paragraph, containing "STRUCTURE_1r9i", creates the "Structure Box" on the page.
+<StructureSection load='1r9i' size='340' side='right'caption='[[1r9i]]' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<table><tr><td colspan='2'>[[1r9i]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Conus_purpurascens Conus purpurascens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1R9I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1R9I FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CY3:2-AMINO-3-MERCAPTO-PROPIONAMIDE'>CY3</scene>, <scene name='pdbligand=HYP:4-HYDROXYPROLINE'>HYP</scene>, <scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</scene></td></tr>
-{{STRUCTURE_1r9i|  PDB=1r9i  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1r9i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1r9i OCA], [https://pdbe.org/1r9i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1r9i RCSB], [https://www.ebi.ac.uk/pdbsum/1r9i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1r9i ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/CM3A_CONPU CM3A_CONPU] Mu-conotoxins block voltage-gated sodium channels (Nav). This toxin potently blocks rNav1.4/SCN4A. It also moderately blocks rNav1.1/SCN1A, rNav1.2/SCN2A, rNav1.3/SCN3A, mNav1.6/SCN8A, and h/rNav1.7/SCN9A. This inhibition is reversible. The block of SCN1A, SCN2A, and SCN8A is modified when beta-subunits are coexpressed with alpha subunits. Hence, blocks of channels containing the beta-1 and beta-3 subunits are more potent (compared to channels without beta subunits), whereas blocks of channels containing the beta-2 and beta-4 are less potent (compared to channels without beta subunits). This peptide causes flaccid paralysis in both mice and fish.<ref>PMID:18950653</ref> <ref>PMID:21652775</ref> <ref>PMID:22229737</ref> <ref>PMID:22407516</ref> <ref>PMID:23146020</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Mu-conotoxins are peptide inhibitors of voltage-sensitive sodium channels (VSSCs). Synthetic forms of mu-conotoxins PIIIA and PIIIA-(2-22) were found to inhibit tetrodotoxin (TTX)-sensitive VSSC current but had little effect on TTX-resistant VSSC current in sensory ganglion neurons. In rat brain neurons, these peptides preferentially inhibited the persistent over the transient VSSC current. Radioligand binding assays revealed that PIIIA, PIIIA-(2-22), and mu-conotoxins GIIIB discriminated among TTX-sensitive VSSCs in rat brain, that these and GIIIC discriminated among the corresponding VSSCs in human brain, and GIIIA had low affinity for neuronal VSSCs. (1)H NMR studies found that PIIIA adopts two conformations in solution due to cis/trans isomerization at hydroxyproline 8. The major trans conformation results in a three-dimensional structure that is significantly different from the previously identified conformation of mu-conotoxins GIIIA and GIIIB that selectively target TTX-sensitive muscle VSSCs. Comparison of the structures and activity of PIIIA to muscle-selective mu-conotoxins provides an insight into the structural requirements for inhibition of different TTX-sensitive sodium channels by mu-conotoxins.
-===NMR Solution Structure of PIIIA toxin, NMR, 20 structures===
+Solution structure of mu-conotoxin PIIIA, a preferential inhibitor of persistent tetrodotoxin-sensitive sodium channels.,Nielsen KJ, Watson M, Adams DJ, Hammarstrom AK, Gage PW, Hill JM, Craik DJ, Thomas L, Adams D, Alewood PF, Lewis RJ J Biol Chem. 2002 Jul 26;277(30):27247-55. Epub 2002 May 2. PMID:12006587<ref>PMID:12006587</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-<!--
+</div>
-The line below this paragraph, {{ABSTRACT_PUBMED_12006587}}, adds the Publication Abstract to the page
+<div class="pdbe-citations 1r9i" style="background-color:#fffaf0;"></div>
-(as it appears on PubMed at http://www.pubmed.gov), where 12006587 is the PubMed ID number.
+== References ==
--->
+<references/>
-{{ABSTRACT_PUBMED_12006587}}
+__TOC__
+</StructureSection>
-==About this Structure==
-R9I is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Conus_purpurascens Conus purpurascens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1R9I OCA].
-==Reference==
-Solution structure of mu-conotoxin PIIIA, a preferential inhibitor of persistent tetrodotoxin-sensitive sodium channels., Nielsen KJ, Watson M, Adams DJ, Hammarstrom AK, Gage PW, Hill JM, Craik DJ, Thomas L, Adams D, Alewood PF, Lewis RJ, J Biol Chem. 2002 Jul 26;277(30):27247-55. Epub 2002 May 2. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/12006587 12006587]
 [[Category: Conus purpurascens]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Adams, D.]]
+[[Category: Adams D]]
-[[Category: Adams, D J.]]
+[[Category: Adams DJ]]
-[[Category: Alewood, P F.]]
+[[Category: Alewood PF]]
-[[Category: Craik, D J.]]
+[[Category: Craik DJ]]
-[[Category: Gage, P W.]]
+[[Category: Gage PW]]
-[[Category: Hammarstrom, A K.]]
+[[Category: Hammarstrom AK]]
-[[Category: Hill, J M.]]
+[[Category: Hill JM]]
-[[Category: Lewis, R J.]]
+[[Category: Lewis RJ]]
-[[Category: Nielsen, K J.]]
+[[Category: Nielsen KJ]]
-[[Category: Thomas, L.]]
+[[Category: Thomas L]]
-[[Category: Watson, M.]]
+[[Category: Watson M]]
-[[Category: Conotoxin]]
-[[Category: Cysteine knot]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 20:29:07 2008''

1r9i

From Proteopedia

Current revision

NMR Solution Structure of PIIIA toxin, NMR, 20 structures

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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