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| - | [[Image:1apf.gif|left|200px]]<br /><applet load="1apf" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1apf" /> | |
| - | '''ANTHOPLEURIN-B, NMR, 20 STRUCTURES'''<br /> | |
| | | | |
| - | ==Overview== | + | ==ANTHOPLEURIN-B, NMR, 20 STRUCTURES== |
| - | BACKGROUND: The polypeptide anthopleurin-B (AP-B) is one of a number of, related toxins produced by sea anemones. AP-B delays inactivation of the, voltage-gated sodium channel of excitable tissue. In the mammalian heart, this effect is manifest as an increase in the force of contraction. As a, result, there is interest in exploiting the anthopleurins as lead, compounds in the design of novel cardiac stimulants. Essential to this, endeavour is a high-resolution solution structure of the molecule, describing the positions of functionally important side chains. RESULTS:, AP-B exists in multiple conformations in solution as a result of cis-trans, isomerization about the Gly40-Pro41 peptide bond. The solution structure, of the major conformer of AP-B has been determined by two-dimensional 1H, NMR at pH 4.5 and 25 degrees C. The core structure is a four-stranded, antiparallel beta-sheet (residues 2-4, 20-23, 34-37 and 45-48) and, includes several beta-turns (6-9, 25-28, 30-33). Three loops connect the, beta-strands, the longest and least well defined being the first loop, extending from residues 8-17. These features are shared by other members, of this family of sea anemone toxins. The locations of a number of side, chains which are important for the cardiac stimulatory activity of AP-B, are well defined in the structures. CONCLUSIONS: We have described the, solution structure of AP-B and compared it with that of AP-A, from which, it differs by substitutions at seven amino acid positions. It shares an, essentially identical fold with AP-A yet is about 10-fold more active., Comparison of the structures, particularly in the region of residues, essential for activity, gives a clearer indication of the location and, extent of the cardioactive pharmacophore in these polypeptides. | + | <StructureSection load='1apf' size='340' side='right'caption='[[1apf]]' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1apf]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Anthopleura_xanthogrammica Anthopleura xanthogrammica]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1APF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1APF FirstGlance]. <br> |
| | + | </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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1apf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1apf OCA], [https://pdbe.org/1apf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1apf RCSB], [https://www.ebi.ac.uk/pdbsum/1apf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1apf ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/NA1B_ANTXA NA1B_ANTXA] Binds specifically to voltage-gated sodium channels (Nav) (site 3), thereby delaying their inactivation. This toxin has the highest affinity of all anemone toxins for the mammalian sodium channel, whereas its paralog Anthopleurin-A retains the greatest capacity to discriminate between cardiac (Nav1.5/SCN5A) and neuronal sodium channels (PubMed:8916901). When tested electrophysiologically, this toxin exhibits a high affinity for multiple sodium channels with a 50-fold preference for rat cardiac (Nav1.5/SCN5A) over neuronal channels (0.1 nM versus 5 nM). When tested by ion flux, the affinities are similar and appear to have higher affinity (9 nM versus 22 nM) (PubMed:7612595, PubMed:8276803). The residue Lys-37 of this toxin has been shown to interact with channel Nav1.5 (residue Asp-1612 in rat and Asp-1610 in human), which is located in the DIV S3-S4 linker (corresponding to channel site 3) (PubMed:24898004, PubMed:9417050). Selectively modifies sodium channel inactivation from the open state with little effect on channel activation or on inactivation from closed states (By similarity). Does not display phospholipid-binding activities, suggesting that the domain IV S3-S4 linker is located at the extracellular surface and not buried in the phospholipid bilayer (PubMed:15632158).[UniProtKB:P01530]<ref>PMID:15632158</ref> <ref>PMID:24898004</ref> <ref>PMID:7612595</ref> <ref>PMID:8276803</ref> <ref>PMID:8916901</ref> <ref>PMID:9306007</ref> <ref>PMID:9417050</ref> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ap/1apf_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1apf ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | BACKGROUND: The polypeptide anthopleurin-B (AP-B) is one of a number of related toxins produced by sea anemones. AP-B delays inactivation of the voltage-gated sodium channel of excitable tissue. In the mammalian heart, this effect is manifest as an increase in the force of contraction. As a result, there is interest in exploiting the anthopleurins as lead compounds in the design of novel cardiac stimulants. Essential to this endeavour is a high-resolution solution structure of the molecule describing the positions of functionally important side chains. RESULTS: AP-B exists in multiple conformations in solution as a result of cis-trans isomerization about the Gly40-Pro41 peptide bond. The solution structure of the major conformer of AP-B has been determined by two-dimensional 1H NMR at pH 4.5 and 25 degrees C. The core structure is a four-stranded, antiparallel beta-sheet (residues 2-4, 20-23, 34-37 and 45-48) and includes several beta-turns (6-9, 25-28, 30-33). Three loops connect the beta-strands, the longest and least well defined being the first loop, extending from residues 8-17. These features are shared by other members of this family of sea anemone toxins. The locations of a number of side chains which are important for the cardiac stimulatory activity of AP-B are well defined in the structures. CONCLUSIONS: We have described the solution structure of AP-B and compared it with that of AP-A, from which it differs by substitutions at seven amino acid positions. It shares an essentially identical fold with AP-A yet is about 10-fold more active. Comparison of the structures, particularly in the region of residues essential for activity, gives a clearer indication of the location and extent of the cardioactive pharmacophore in these polypeptides. |
| | | | |
| - | ==About this Structure==
| + | Solution structure of the cardiostimulant polypeptide anthopleurin-B and comparison with anthopleurin-A.,Monks SA, Pallaghy PK, Scanlon MJ, Norton RS Structure. 1995 Aug 15;3(8):791-803. PMID:7582896<ref>PMID:7582896</ref> |
| - | 1APF is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Anthopleura_xanthogrammica Anthopleura xanthogrammica]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1APF OCA].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | Solution structure of the cardiostimulant polypeptide anthopleurin-B and comparison with anthopleurin-A., Monks SA, Pallaghy PK, Scanlon MJ, Norton RS, Structure. 1995 Aug 15;3(8):791-803. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=7582896 7582896]
| + | </div> |
| | + | <div class="pdbe-citations 1apf" style="background-color:#fffaf0;"></div> |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Anthopleura xanthogrammica]] | | [[Category: Anthopleura xanthogrammica]] |
| - | [[Category: Single protein]] | + | [[Category: Large Structures]] |
| - | [[Category: Monks, S.A.]] | + | [[Category: Monks SA]] |
| - | [[Category: Norton, R.S.]] | + | [[Category: Norton RS]] |
| - | [[Category: Pallaghy, P.K.]] | + | [[Category: Pallaghy PK]] |
| - | [[Category: Scanlon, M.J.]] | + | [[Category: Scanlon MJ]] |
| - | [[Category: cardiac stimulant]]
| + | |
| - | [[Category: sea anemone]]
| + | |
| - | [[Category: toxin]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 11:01:23 2007''
| + | |
| Structural highlights
Function
NA1B_ANTXA Binds specifically to voltage-gated sodium channels (Nav) (site 3), thereby delaying their inactivation. This toxin has the highest affinity of all anemone toxins for the mammalian sodium channel, whereas its paralog Anthopleurin-A retains the greatest capacity to discriminate between cardiac (Nav1.5/SCN5A) and neuronal sodium channels (PubMed:8916901). When tested electrophysiologically, this toxin exhibits a high affinity for multiple sodium channels with a 50-fold preference for rat cardiac (Nav1.5/SCN5A) over neuronal channels (0.1 nM versus 5 nM). When tested by ion flux, the affinities are similar and appear to have higher affinity (9 nM versus 22 nM) (PubMed:7612595, PubMed:8276803). The residue Lys-37 of this toxin has been shown to interact with channel Nav1.5 (residue Asp-1612 in rat and Asp-1610 in human), which is located in the DIV S3-S4 linker (corresponding to channel site 3) (PubMed:24898004, PubMed:9417050). Selectively modifies sodium channel inactivation from the open state with little effect on channel activation or on inactivation from closed states (By similarity). Does not display phospholipid-binding activities, suggesting that the domain IV S3-S4 linker is located at the extracellular surface and not buried in the phospholipid bilayer (PubMed:15632158).[UniProtKB:P01530][1] [2] [3] [4] [5] [6] [7]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
BACKGROUND: The polypeptide anthopleurin-B (AP-B) is one of a number of related toxins produced by sea anemones. AP-B delays inactivation of the voltage-gated sodium channel of excitable tissue. In the mammalian heart, this effect is manifest as an increase in the force of contraction. As a result, there is interest in exploiting the anthopleurins as lead compounds in the design of novel cardiac stimulants. Essential to this endeavour is a high-resolution solution structure of the molecule describing the positions of functionally important side chains. RESULTS: AP-B exists in multiple conformations in solution as a result of cis-trans isomerization about the Gly40-Pro41 peptide bond. The solution structure of the major conformer of AP-B has been determined by two-dimensional 1H NMR at pH 4.5 and 25 degrees C. The core structure is a four-stranded, antiparallel beta-sheet (residues 2-4, 20-23, 34-37 and 45-48) and includes several beta-turns (6-9, 25-28, 30-33). Three loops connect the beta-strands, the longest and least well defined being the first loop, extending from residues 8-17. These features are shared by other members of this family of sea anemone toxins. The locations of a number of side chains which are important for the cardiac stimulatory activity of AP-B are well defined in the structures. CONCLUSIONS: We have described the solution structure of AP-B and compared it with that of AP-A, from which it differs by substitutions at seven amino acid positions. It shares an essentially identical fold with AP-A yet is about 10-fold more active. Comparison of the structures, particularly in the region of residues essential for activity, gives a clearer indication of the location and extent of the cardioactive pharmacophore in these polypeptides.
Solution structure of the cardiostimulant polypeptide anthopleurin-B and comparison with anthopleurin-A.,Monks SA, Pallaghy PK, Scanlon MJ, Norton RS Structure. 1995 Aug 15;3(8):791-803. PMID:7582896[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Smith JJ, Alphy S, Seibert AL, Blumenthal KM. Differential phospholipid binding by site 3 and site 4 toxins. Implications for structural variability between voltage-sensitive sodium channel domains. J Biol Chem. 2005 Mar 25;280(12):11127-33. PMID:15632158 doi:10.1074/jbc.M412552200
- ↑ Xiao Y, Blumenthal K, Cummins TR. Gating-pore currents demonstrate selective and specific modulation of individual sodium channel voltage-sensors by biological toxins. Mol Pharmacol. 2014 Aug;86(2):159-67. PMID:24898004 doi:10.1124/mol.114.092338
- ↑ Khera PK, Benzinger GR, Lipkind G, Drum CL, Hanck DA, Blumenthal KM. Multiple cationic residues of anthopleurin B that determine high affinity and channel isoform discrimination. Biochemistry. 1995 Jul 11;34(27):8533-41. PMID:7612595 doi:10.1021/bi00027a003
- ↑ Gallagher MJ, Blumenthal KM. Importance of the unique cationic residues arginine 12 and lysine 49 in the activity of the cardiotonic polypeptide anthopleurin B. J Biol Chem. 1994 Jan 7;269(1):254-9 PMID:8276803
- ↑ Kelso GJ, Drum CL, Hanck DA, Blumenthal KM. Role for Pro-13 in directing high-affinity binding of anthopleurin B to the voltage-sensitive sodium channel. Biochemistry. 1996 Nov 12;35(45):14157-64. PMID:8916901 doi:10.1021/bi961584d
- ↑ Benzinger GR, Drum CL, Chen LQ, Kallen RG, Hanck DA, Hanck D. Differences in the binding sites of two site-3 sodium channel toxins. Pflugers Arch. 1997 Nov;434(6):742-9. PMID:9306007 doi:10.1007/s004240050460
- ↑ Benzinger GR, Kyle JW, Blumenthal KM, Hanck DA. A specific interaction between the cardiac sodium channel and site-3 toxin anthopleurin B. J Biol Chem. 1998 Jan 2;273(1):80-4. PMID:9417050 doi:10.1074/jbc.273.1.80
- ↑ Monks SA, Pallaghy PK, Scanlon MJ, Norton RS. Solution structure of the cardiostimulant polypeptide anthopleurin-B and comparison with anthopleurin-A. Structure. 1995 Aug 15;3(8):791-803. PMID:7582896
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