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==THE NMR SOLUTION STRUCTURE OF THE COMPLEX FORMED BETWEEN ALPHA-BUNGAROTOXIN AND AN 18MER COGNATE PEPTIDE==
==THE NMR SOLUTION STRUCTURE OF THE COMPLEX FORMED BETWEEN ALPHA-BUNGAROTOXIN AND AN 18MER COGNATE PEPTIDE==
<StructureSection load='1idh' size='340' side='right'caption='[[1idh]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
<StructureSection load='1idh' size='340' side='right'caption='[[1idh]]' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1idh]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bungarus_multicinctus Bungarus multicinctus] and [https://en.wikipedia.org/wiki/Pacific_electric_ray Pacific electric ray]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1IDH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1IDH FirstGlance]. <br>
<table><tr><td colspan='2'>[[1idh]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bungarus_multicinctus Bungarus multicinctus] and [https://en.wikipedia.org/wiki/Tetronarce_californica Tetronarce californica]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1IDH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1IDH 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;'>[[1idg|1idg]], [[1idi|1idi]], [[1idl|1idl]]</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=1idh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1idh OCA], [https://pdbe.org/1idh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1idh RCSB], [https://www.ebi.ac.uk/pdbsum/1idh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1idh 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=1idh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1idh OCA], [https://pdbe.org/1idh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1idh RCSB], [https://www.ebi.ac.uk/pdbsum/1idh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1idh 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/ACHA_TORCA ACHA_TORCA]] 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=1idh 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=1idh ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The region encompassing residues 181-98 on the alpha1 subunit of the muscle-type nicotinic acetylcholine receptor forms a major determinant for the binding of alpha-neurotoxins. We have prepared an (15)N-enriched 18-amino acid peptide corresponding to the sequence in this region to facilitate structural elucidation by multidimensional NMR. Our aim was to determine the structural basis for the high affinity, stoichiometric complex formed between this cognate peptide and alpha-bungarotoxin, a long alpha-neurotoxin. Resonances in the complex were assigned through heteronuclear and homonuclear NMR experiments, and the resulting interproton distance constraints were used to generate ensemble structures of the complex. Thr(8), Pro(10), Lys(38), Val(39), Val(40), and Pro(69) in alpha-bungarotoxin and Tyr(189), Tyr(190), Thr(191), Cys(192), Asp(195), and Thr(196) in the peptide participate in major intermolecular contacts. A comparison of the free and bound alpha-bungarotoxin structures reveals significant conformational rearrangements in flexible regions of alpha-bungarotoxin, mainly loops I, II, and the C-terminal tail. Furthermore, several of the calculated structures suggest that cation-pi interactions may be involved in binding. The root mean square deviation of the polypeptide backbone in the complex is 2.07 A. This structure provides, to date, the highest resolution description of the contacts between a prototypic alpha-neurotoxin and its cognate recognition sequence.
The solution structure of the complex formed between alpha-bungarotoxin and an 18-mer cognate peptide derived from the alpha 1 subunit of the nicotinic acetylcholine receptor from Torpedo californica.,Zeng H, Moise L, Grant MA, Hawrot E J Biol Chem. 2001 Jun 22;276(25):22930-40. Epub 2001 Apr 18. PMID:11312275<ref>PMID:11312275</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1idh" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
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[[Category: Bungarus multicinctus]]
[[Category: Bungarus multicinctus]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Pacific electric ray]]
[[Category: Tetronarce californica]]
[[Category: Grant, M A]]
[[Category: Grant MA]]
[[Category: Hawrot, E]]
[[Category: Hawrot E]]
[[Category: Moise, L]]
[[Category: Moise L]]
[[Category: Zeng, H]]
[[Category: Zeng H]]
[[Category: Alpha 1 subunit]]
[[Category: Alpha-bungarotoxin]]
[[Category: Cation-pi interaction]]
[[Category: Nicotinic acetylcholine receptor]]
[[Category: Protein-protein interaction]]
[[Category: Toxin]]

Latest revision as of 10:46, 3 April 2024

THE NMR SOLUTION STRUCTURE OF THE COMPLEX FORMED BETWEEN ALPHA-BUNGAROTOXIN AND AN 18MER COGNATE PEPTIDETHE NMR SOLUTION STRUCTURE OF THE COMPLEX FORMED BETWEEN ALPHA-BUNGAROTOXIN AND AN 18MER COGNATE PEPTIDE

Structural highlights

1idh is a 2 chain structure with sequence from Bungarus multicinctus and Tetronarce californica. 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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