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==NMR STRUCTURAL ANALYSIS OF THE COMPLEX FORMED BETWEEN ALPHA-BUNGAROTOXIN AND THE PRINCIPAL ALPHA-NEUROTOXIN BINDING SEQUENCE ON THE ALPHA7 SUBUNIT OF A NEURONAL NICOTINIC ACETYLCHOLINE RECEPTOR==
==NMR STRUCTURAL ANALYSIS OF THE COMPLEX FORMED BETWEEN ALPHA-BUNGAROTOXIN AND THE PRINCIPAL ALPHA-NEUROTOXIN BINDING SEQUENCE ON THE ALPHA7 SUBUNIT OF A NEURONAL NICOTINIC ACETYLCHOLINE RECEPTOR==
<StructureSection load='1kl8' size='340' side='right'caption='[[1kl8]], [[NMR_Ensembles_of_Models | 1 NMR models]]' scene=''>
<StructureSection load='1kl8' size='340' side='right'caption='[[1kl8]]' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1kl8]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bunmu Bunmu] and [https://en.wikipedia.org/wiki/Chick Chick]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1KL8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1KL8 FirstGlance]. <br>
<table><tr><td colspan='2'>[[1kl8]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bungarus_multicinctus Bungarus multicinctus] and [https://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1KL8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1KL8 FirstGlance]. <br>
</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=HSL:HOMOSERINE+LACTONE'>HSL</scene></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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1abt|1abt]], [[1idh|1idh]], [[2abx|2abx]], [[1i9b|1i9b]], [[1hc9|1hc9]], [[1jbd|1jbd]], [[1kc4|1kc4]], [[1kfh|1kfh]], [[1haj|1haj]], [[1bxp|1bxp]], [[1ikc|1ikc]]</div></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HSL:HOMOSERINE+LACTONE'>HSL</scene></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=1kl8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1kl8 OCA], [https://pdbe.org/1kl8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1kl8 RCSB], [https://www.ebi.ac.uk/pdbsum/1kl8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1kl8 ProSAT]</span></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=1kl8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1kl8 OCA], [https://pdbe.org/1kl8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1kl8 RCSB], [https://www.ebi.ac.uk/pdbsum/1kl8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1kl8 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[https://www.uniprot.org/uniprot/NXL1A_BUNMU NXL1A_BUNMU]] Binds with high affinity to muscular and neuronal (alpha-7, alpha-8, and alpha-9) nicotinic acetylcholine receptors. Produces peripheral paralysis by blocking neuromuscular transmission at the postsynaptic site. Blocks the extracellular increase of dopamine evoked by nicotine only at the higher dose (4.2 uM).<ref>PMID:9305882</ref> <ref>PMID:9840221</ref> [[https://www.uniprot.org/uniprot/ACHA7_CHICK ACHA7_CHICK]] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
[https://www.uniprot.org/uniprot/3L21A_BUNMU 3L21A_BUNMU] Binds with high affinity to muscular (tested on Torpedo marmorata, Kd=0.4 nM) and neuronal (tested on chimeric alpha-7/CHRNA7, Kd=0.95 nM) nicotinic acetylcholine receptor (nAChR) and inhibits acetylcholine from binding to the receptor, thereby impairing neuromuscular and neuronal transmission (PubMed:9305882). It also shows an activity on GABA(A) receptors (PubMed:16549768, PubMed:25634239). It antagonises GABA-activated currents with high potency when tested on primary hippocampal neurons (PubMed:25634239). It inhibits recombinantly expressed GABA(A) receptors composed of alpha-2-beta-2-gamma-2 (GABRA2-GABRB2-GABRG2) subunits with high potency (62.3% inhibition at 20 uM of toxin) (PubMed:25634239). It also shows a weaker inhibition on GABA(A) receptors composed of alpha-1-beta-2-gamma-2 (GABRA1-GABRB2-GABRG2) subunits, alpha-4-beta-2-gamma-2 (GABRA4-GABRB2-GABRG2) subunits, and alpha-5-beta-2-gamma-2 (GABRA5-GABRB2-GABRG2) subunits (PubMed:25634239). A very weak inhibition is also observed on GABA(A) receptor composed of alpha-1-beta-3-gamma-2 (GABRA1-GABRB3-GABRG2) (PubMed:26221036). It has also been shown to bind and inhibit recombinant GABA(A) receptor beta-3/GABRB3 subunit (Kd=about 50 nM) (PubMed:16549768). In addition, it blocks the extracellular increase of dopamine evoked by nicotine only at the higher dose (4.2 uM) (PubMed:9840221).<ref>PMID:16549768</ref> <ref>PMID:25634239</ref> <ref>PMID:9305882</ref> <ref>PMID:9840221</ref>
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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</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=1kl8 ConSurf].
</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=1kl8 ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
We report a new, higher resolution NMR structure of alpha-bungarotoxin that defines the structure-determining disulfide core and beta-sheet regions. We further report the NMR structure of the stoichiometric complex formed between alpha-bungarotoxin and a recombinantly expressed 19-mer peptide ((178)IPGKRTESFYECCKEPYPD(196)) derived from the alpha7 subunit of the chick neuronal nicotinic acetylcholine receptor. A comparison of these two structures reveals binding-induced stabilization of the flexible tip of finger II in alpha-bungarotoxin. The conformational rearrangements in the toxin create an extensive binding surface involving both sides of the alpha7 19-mer hairpin-like structure. At the contact zone, Ala(7), Ser(9), and Ile(11) in finger I and Arg(36), Lys(38), Val(39), and Val(40) in finger II of alpha-bungarotoxin interface with Phe(186), Tyr(187), Glu(188), and Tyr(194) in the alpha7 19-mer underscoring the importance of receptor aromatic residues as critical neurotoxin-binding determinants. Superimposing the structure of the complex onto that of the acetylcholine-binding protein (1I9B), a soluble homologue of the extracellular domain of the alpha7 receptor, places alpha-bungarotoxin at the peripheral surface of the inter-subunit interface occluding the agonist-binding site. The disulfide-rich core of alpha-bungarotoxin is suggested to be tilted in the direction of the membrane surface with finger II extending into the proposed ligand-binding cavity.
NMR structural analysis of alpha-bungarotoxin and its complex with the principal alpha-neurotoxin-binding sequence on the alpha 7 subunit of a neuronal nicotinic acetylcholine receptor.,Moise L, Piserchio A, Basus VJ, Hawrot E J Biol Chem. 2002 Apr 5;277(14):12406-17. Epub 2002 Jan 14. PMID:11790782<ref>PMID:11790782</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1kl8" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Bunmu]]
[[Category: Bungarus multicinctus]]
[[Category: Chick]]
[[Category: Gallus gallus]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Basus, V J]]
[[Category: Basus VJ]]
[[Category: Hawrot, E]]
[[Category: Hawrot E]]
[[Category: Moise, L]]
[[Category: Moise L]]
[[Category: Piserchio, A]]
[[Category: Piserchio A]]
[[Category: Alpha-bungarotoxin]]
[[Category: Alpha-neurotoxin]]
[[Category: Ligand-gated ion channel]]
[[Category: Nicotinic acetylcholine receptor alpha 7 subunit]]
[[Category: Nmr protein-protein interaction]]
[[Category: Protein-peptide complex]]
[[Category: Toxin]]

Latest revision as of 11:01, 3 April 2024

NMR STRUCTURAL ANALYSIS OF THE COMPLEX FORMED BETWEEN ALPHA-BUNGAROTOXIN AND THE PRINCIPAL ALPHA-NEUROTOXIN BINDING SEQUENCE ON THE ALPHA7 SUBUNIT OF A NEURONAL NICOTINIC ACETYLCHOLINE RECEPTORNMR STRUCTURAL ANALYSIS OF THE COMPLEX FORMED BETWEEN ALPHA-BUNGAROTOXIN AND THE PRINCIPAL ALPHA-NEUROTOXIN BINDING SEQUENCE ON THE ALPHA7 SUBUNIT OF A NEURONAL NICOTINIC ACETYLCHOLINE RECEPTOR

Structural highlights

1kl8 is a 2 chain structure with sequence from Bungarus multicinctus and Gallus gallus. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

3L21A_BUNMU Binds with high affinity to muscular (tested on Torpedo marmorata, Kd=0.4 nM) and neuronal (tested on chimeric alpha-7/CHRNA7, Kd=0.95 nM) nicotinic acetylcholine receptor (nAChR) and inhibits acetylcholine from binding to the receptor, thereby impairing neuromuscular and neuronal transmission (PubMed:9305882). It also shows an activity on GABA(A) receptors (PubMed:16549768, PubMed:25634239). It antagonises GABA-activated currents with high potency when tested on primary hippocampal neurons (PubMed:25634239). It inhibits recombinantly expressed GABA(A) receptors composed of alpha-2-beta-2-gamma-2 (GABRA2-GABRB2-GABRG2) subunits with high potency (62.3% inhibition at 20 uM of toxin) (PubMed:25634239). It also shows a weaker inhibition on GABA(A) receptors composed of alpha-1-beta-2-gamma-2 (GABRA1-GABRB2-GABRG2) subunits, alpha-4-beta-2-gamma-2 (GABRA4-GABRB2-GABRG2) subunits, and alpha-5-beta-2-gamma-2 (GABRA5-GABRB2-GABRG2) subunits (PubMed:25634239). A very weak inhibition is also observed on GABA(A) receptor composed of alpha-1-beta-3-gamma-2 (GABRA1-GABRB3-GABRG2) (PubMed:26221036). It has also been shown to bind and inhibit recombinant GABA(A) receptor beta-3/GABRB3 subunit (Kd=about 50 nM) (PubMed:16549768). In addition, it blocks the extracellular increase of dopamine evoked by nicotine only at the higher dose (4.2 uM) (PubMed:9840221).[1] [2] [3] [4]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

References

  1. ↑ McCann CM, Bracamontes J, Steinbach JH, Sanes JR. The cholinergic antagonist alpha-bungarotoxin also binds and blocks a subset of GABA receptors. Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5149-54. doi:, 10.1073/pnas.0600847103. Epub 2006 Mar 20. PMID:16549768 doi:http://dx.doi.org/10.1073/pnas.0600847103
  2. ↑ Hannan S, Mortensen M, Smart TG. Snake neurotoxin alpha-bungarotoxin is an antagonist at native GABA(A) receptors. Neuropharmacology. 2015 Jun;93:28-40. doi: 10.1016/j.neuropharm.2015.01.001. Epub, 2015 Jan 26. PMID:25634239 doi:http://dx.doi.org/10.1016/j.neuropharm.2015.01.001
  3. ↑ Servent D, Winckler-Dietrich V, Hu HY, Kessler P, Drevet P, Bertrand D, Menez A. Only snake curaremimetic toxins with a fifth disulfide bond have high affinity for the neuronal alpha7 nicotinic receptor. J Biol Chem. 1997 Sep 26;272(39):24279-86. PMID:9305882
  4. ↑ Dajas-Bailador F, Costa G, Dajas F, Emmett S. Effects of alpha-erabutoxin, alpha-bungarotoxin, alpha-cobratoxin and fasciculin on the nicotine-evoked release of dopamine in the rat striatum in vivo. Neurochem Int. 1998 Oct;33(4):307-12. PMID:9840221
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