1apf

From Proteopedia

(Difference between revisions)

Current revision

ANTHOPLEURIN-B, NMR, 20 STRUCTURES

Structural highlights

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

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

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 4: / Line 4: @@
 == 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</td></tr>
+</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:8276803, PubMed:7612595). 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:9417050, PubMed:24898004). 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>
+[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]]
@@ Line 14: / Line 14: @@
   <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/initialview01.spt</scriptWhenUnchecked>
+    <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.
+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>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 1apf" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

1apf

From Proteopedia

Current revision

ANTHOPLEURIN-B, NMR, 20 STRUCTURES

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

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