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2mub

From Proteopedia

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Solution structure of the analgesic sea anemone peptide APETx2

Structural highlights

2mub is a 1 chain structure with sequence from Anthopleura elegantissima. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BDS2_ANTEL This toxin potently blocks acid-sensing ion channel ASIC3 homotrimers and heterotrimers containing ASIC3 (composed with isoforms of ASIC1 and ASIC2) (PubMed:15044953). It also weakly inhibits potassium channels, and sodium channels (PubMed:15044953, PubMed:21943094, PubMed:22972919, PubMed:25337890). On homomeric ASIC3, this protein shows IC(50)=57-87 nM on rat, 37.3 nM on mouse and 175 nM on human channels (PubMed:15044953, PubMed:18923424, PubMed:19306891, PubMed:20813121, PubMed:21943094, PubMed:22851922, PubMed:22851929). The blockade is rapid and reversible (PubMed:15044953). On heterotrimeric forms, the toxin is less potent (IC(50)=117 nM on rat ASIC2b-ASIC3 channel, 900 nM on rat ASIC1b-ASIC3, and 2 uM on rat ASIC1a-ASIC3) (PubMed:15044953). It weakly inhibits Kv3.4/KCNC4 potassium channels (3 uM of the toxin inhibits 38% of Kv3.4 current) (PubMed:15044953). It reversibly and voltage-dependently inhibits hKv11.1/KCNH2/ERG1 potassium channels (IC(50)=1.21 uM), inhibiting both peak and tail currents without action on channel inactivation (PubMed:25337890). It weakly inhibits rNav1.2/SCN2A (EC(50)=114 nM), rNav1.6/SCN8A current (17% at 1 uM of the toxin) and Nav1.8/SCN10A (IC(50)=6.6 uM on human channels expressed in oocytes, EC(50)=55 nM on rat channels expressed in oocytes, and 2.6 uM on rat channels in DRG neurons) (PubMed:21943094, PubMed:22972919). It may act on sodium channels by binding at site 1 or close by, when the pore is in an open configuration (PubMed:22972919). In vivo, central injection does not induce neurotoxin symptoms in mice even after 24 hours (PubMed:15044953). However, it abolishes acid-induced pain in rats (PubMed:18923424).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9]

Publication Abstract from PubMed

The sea anemone peptide APETx2 is a potent and selective blocker of acid-sensing ion channel 3 (ASIC3). APETx2 is analgesic in a variety of rodent pain models, but the lack of knowledge of its pharmacophore and binding site on ASIC3 has impeded development of improved analogues. Here we present a detailed structure-activity relationship study of APETx2. Determination of a high-resolution structure of APETx2 combined with scanning mutagenesis revealed a cluster of aromatic and basic residues that mediate its interaction with ASIC3. We show that APETx2 also inhibits the off-target hERG channel by reducing the maximal current amplitude and shifting the voltage dependence of activation to more positive potentials. Electrophysiological screening of selected APETx2 mutants revealed partial overlap between the surfaces on APETx2 that mediate its interaction with ASIC3 and hERG. Characterization of the molecular basis of these interactions is an important first step toward the rational design of more selective APETx2 analogues.

Understanding the Molecular Basis of Toxin Promiscuity: The Analgesic Sea Anemone Peptide APETx2 Interacts with Acid-Sensing Ion Channel 3 and hERG Channels via Overlapping Pharmacophores.,Jensen JE, Cristofori-Armstrong B, Anangi R, Rosengren KJ, Lau CH, Mobli M, Brust A, Alewood PF, King GF, Rash LD J Med Chem. 2014 Nov 13;57(21):9195-203. doi: 10.1021/jm501400p. Epub 2014 Nov 4. PMID:25337890^[10]

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

References

↑ Diochot S, Baron A, Rash LD, Deval E, Escoubas P, Scarzello S, Salinas M, Lazdunski M. A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons. EMBO J. 2004 Apr 7;23(7):1516-25. Epub 2004 Mar 25. PMID:15044953 doi:http://dx.doi.org/10.1038/sj.emboj.7600177
↑ Deval E, Noël J, Lay N, Alloui A, Diochot S, Friend V, Jodar M, Lazdunski M, Lingueglia E. ASIC3, a sensor of acidic and primary inflammatory pain. EMBO J. 2008 Nov 19;27(22):3047-55. PMID:18923424 doi:10.1038/emboj.2008.213
↑ Jensen JE, Durek T, Alewood PF, Adams DJ, King GF, Rash LD. Chemical synthesis and folding of APETx2, a potent and selective inhibitor of acid sensing ion channel 3. Toxicon. 2009 Jul;54(1):56-61. PMID:19306891 doi:10.1016/j.toxicon.2009.03.014
↑ Anangi R, Chen CC, Lin YW, Cheng YR, Cheng CH, Chen YC, Chu YP, Chuang WJ. Expression in Pichia pastoris and characterization of APETx2, a specific inhibitor of acid sensing ion channel 3. Toxicon. 2010 Dec;56(8):1388-97. PMID:20813121 doi:10.1016/j.toxicon.2010.08.004
↑ Blanchard MG, Rash LD, Kellenberger S. Inhibition of voltage-gated Na(+) currents in sensory neurones by the sea anemone toxin APETx2. Br J Pharmacol. 2012 Apr;165(7):2167-77. PMID:21943094 doi:10.1111/j.1476-5381.2011.01674.x
↑ Jensen JE, Mobli M, Brust A, Alewood PF, King GF, Rash LD. Cyclisation increases the stability of the sea anemone peptide APETx2 but decreases its activity at acid-sensing ion channel 3. Mar Drugs. 2012 Jul;10(7):1511-1527. PMID:22851922 doi:10.3390/md10071511
↑ Anangi R, Rash LD, Mobli M, King GF. Functional expression in Escherichia coli of the disulfide-rich sea anemone peptide APETx2, a potent blocker of acid-sensing ion channel 3. Mar Drugs. 2012 Jul;10(7):1605-1618. PMID:22851929 doi:10.3390/md10071605
↑ Peigneur S, Beress L, Moller C, Mari F, Forssmann WG, Tytgat J. A natural point mutation changes both target selectivity and mechanism of action of sea anemone toxins. FASEB J. 2012 Dec;26(12):5141-51. doi: 10.1096/fj.12-218479. Epub 2012 Sep 12. PMID:22972919 doi:http://dx.doi.org/10.1096/fj.12-218479
↑ Jensen JE, Cristofori-Armstrong B, Anangi R, Rosengren KJ, Lau CH, Mobli M, Brust A, Alewood PF, King GF, Rash LD. Understanding the Molecular Basis of Toxin Promiscuity: The Analgesic Sea Anemone Peptide APETx2 Interacts with Acid-Sensing Ion Channel 3 and hERG Channels via Overlapping Pharmacophores. J Med Chem. 2014 Nov 13;57(21):9195-203. doi: 10.1021/jm501400p. Epub 2014 Nov 4. PMID:25337890 doi:http://dx.doi.org/10.1021/jm501400p
↑ Jensen JE, Cristofori-Armstrong B, Anangi R, Rosengren KJ, Lau CH, Mobli M, Brust A, Alewood PF, King GF, Rash LD. Understanding the Molecular Basis of Toxin Promiscuity: The Analgesic Sea Anemone Peptide APETx2 Interacts with Acid-Sensing Ion Channel 3 and hERG Channels via Overlapping Pharmacophores. J Med Chem. 2014 Nov 13;57(21):9195-203. doi: 10.1021/jm501400p. Epub 2014 Nov 4. PMID:25337890 doi:http://dx.doi.org/10.1021/jm501400p

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/2mub"

@@ Line 1: / Line 1: @@
 ==Solution structure of the analgesic sea anemone peptide APETx2==
-<StructureSection load='2mub' size='340' side='right' caption='[[2mub]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='2mub' size='340' side='right'caption='[[2mub]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2mub]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MUB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2MUB FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2mub]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Anthopleura_elegantissima Anthopleura elegantissima]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MUB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2MUB FirstGlance]. <br>
-</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1wxn|1wxn]]</td></tr>
+</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=2mub FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mub OCA], [https://pdbe.org/2mub PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2mub RCSB], [https://www.ebi.ac.uk/pdbsum/2mub PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2mub ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2mub FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mub OCA], [http://pdbe.org/2mub PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2mub RCSB], [http://www.ebi.ac.uk/pdbsum/2mub PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2mub ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/APT2_ANTEL APT2_ANTEL]] Potently and selectively blocks the acid-sensing ion channel ASIC3 (ACCN3). The blockade is rapid and reversible. Also inhibits heteromeric ASIC2b-ASIC3 (ACCN1-ACCN3) channel, while it has less affinity for ASIC1b-ASIC3 (ACCN2-ACCN3), ASIC1a-ASIC3 (ACCN2-ASIC3).<ref>PMID:15044953</ref>
+[https://www.uniprot.org/uniprot/BDS2_ANTEL BDS2_ANTEL] This toxin potently blocks acid-sensing ion channel ASIC3 homotrimers and heterotrimers containing ASIC3 (composed with isoforms of ASIC1 and ASIC2) (PubMed:15044953). It also weakly inhibits potassium channels, and sodium channels (PubMed:15044953, PubMed:21943094, PubMed:22972919, PubMed:25337890). On homomeric ASIC3, this protein shows IC(50)=57-87 nM on rat, 37.3 nM on mouse and 175 nM on human channels (PubMed:15044953, PubMed:18923424, PubMed:19306891, PubMed:20813121, PubMed:21943094, PubMed:22851922, PubMed:22851929). The blockade is rapid and reversible (PubMed:15044953). On heterotrimeric forms, the toxin is less potent (IC(50)=117 nM on rat ASIC2b-ASIC3 channel, 900 nM on rat ASIC1b-ASIC3, and 2 uM on rat ASIC1a-ASIC3) (PubMed:15044953). It weakly inhibits Kv3.4/KCNC4 potassium channels (3 uM of the toxin inhibits 38% of Kv3.4 current) (PubMed:15044953). It reversibly and voltage-dependently inhibits hKv11.1/KCNH2/ERG1 potassium channels (IC(50)=1.21 uM), inhibiting both peak and tail currents without action on channel inactivation (PubMed:25337890). It weakly inhibits rNav1.2/SCN2A (EC(50)=114 nM), rNav1.6/SCN8A current (17% at 1 uM of the toxin) and Nav1.8/SCN10A (IC(50)=6.6 uM on human channels expressed in oocytes, EC(50)=55 nM on rat channels expressed in oocytes, and 2.6 uM on rat channels in DRG neurons) (PubMed:21943094, PubMed:22972919). It may act on sodium channels by binding at site 1 or close by, when the pore is in an open configuration (PubMed:22972919). In vivo, central injection does not induce neurotoxin symptoms in mice even after 24 hours (PubMed:15044953). However, it abolishes acid-induced pain in rats (PubMed:18923424).<ref>PMID:15044953</ref> <ref>PMID:18923424</ref> <ref>PMID:19306891</ref> <ref>PMID:20813121</ref> <ref>PMID:21943094</ref> <ref>PMID:22851922</ref> <ref>PMID:22851929</ref> <ref>PMID:22972919</ref> <ref>PMID:25337890</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 21: @@
 __TOC__
 </StructureSection>
-[[Category: Jensen, J E]]
+[[Category: Anthopleura elegantissima]]
-[[Category: King, G F]]
+[[Category: Large Structures]]
-[[Category: Mobli, M]]
+[[Category: Jensen JE]]
-[[Category: Rosengren, K J]]
+[[Category: King GF]]
-[[Category: Asic3 blocker]]
+[[Category: Mobli M]]
-[[Category: Defensin fold]]
+[[Category: Rosengren KJ]]
-[[Category: Disulfide-rich toxin]]
-[[Category: Toxin]]

2mub

From Proteopedia

Current revision

Solution structure of the analgesic sea anemone peptide APETx2

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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