4aea

From Proteopedia

(Difference between revisions)

Revision as of 11:24, 20 December 2023

Dimeric alpha-cobratoxin X-ray structure: Localization of intermolecular disulfides and possible mode of binding to nicotinic acetylcholine receptors

Structural highlights

4aea is a 2 chain structure with sequence from Naja kaouthia. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.94Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

3L21_NAJKA Monomer: binds with high affinity to muscular (alpha-1-beta-1-gamma-delta/CHRNA1-CHRNB1-CHRNG-CHRND) nAChR (tested on Torpedo californica, Kd=0.2-4.5 nM) and neuronal alpha-7/CHRNA7 nicotinic acetylcholine receptors (Kd=13-105 nM) (PubMed:18381281, PubMed:9305882, PubMed:22223648). Also inhibits GABA(A) channels (PubMed:26221036). Heteropentamer targets studied are composed of alpha-1-beta-3-gamma-2 (GABRA1-GABRB3-GABRG2) subunits (IC(50)=236 nM), alpha-1-beta-2-gamma-2 (GABRA1-GABRB2-GABRG2) subunits (IC(50)=469 nM), alpha-2-beta-2-gamma-2 (GABRA2-GABRB2-GABRG2) subunits (IC(50)=485 nM), alpha-5-beta-3-gamma-2 (GABRA5-GABRB3-GABRG2) subunits (IC(50)=635 nM), and alpha-2-beta-3-gamma-2 (GABRA2-GABRB3-GABRG2) subunits (IC(50)=1099 nM) (activated by 10 uM GABA) (PubMed:26221036).^[1] ^[2] ^[3] ^[4] Homodimer: binds with high affinity (but lower than the monomeric form) to muscular (IC(50)=9.7 nM) and with low affinity to neuronal alpha-7/CHRNA7 nAChRs (IC(50)=1370 nM) (PubMed:22223648). However, it acquires (compared to the monomeric form) the capacity to block alpha-3/beta-2 (CHRNA3/CHRNB2) nAChRs (PubMed:18381281).^[5] ^[6] Heterodimer with cytotoxin 3 (AC P01446): is slightly more active than the homodimer in inhibiting alpha-7/CHRNA7 nAChR and is considerably more active in blocking the alpha-3-beta-2/CHRNA3-CHRNB2 nAChR.^[7]

Publication Abstract from PubMed

In Naja kaouthia cobra venom, we have earlier discovered a covalent dimeric form of alpha-cobratoxin (alphaCT-alphaCT) with two intermolecular disulfides, but we could not determine their positions. Here, we report the alphaCT-alphaCT crystal structure at 1.94 A where intermolecular disulfides are identified between Cys(3) in one protomer and Cys(20) of the second, and vice versa. All remaining intramolecular disulfides, including the additional bridge between Cys(26) and Cys(30) in the central loops II, have the same positions as in monomeric alpha-cobratoxin. The three-finger fold is essentially preserved in each protomer, but the arrangement of the alphaCT-alphaCT dimer differs from those of noncovalent crystallographic dimers of three-finger toxins (TFT) or from the kappa-bungarotoxin solution structure. Selective reduction of Cys(26)-Cys(30) in one protomer does not affect the activity against the alpha7 nicotinic acetylcholine receptor (nAChR), whereas its reduction in both protomers almost prevents alpha7 nAChR recognition. On the contrary, reduction of one or both Cys(26)-Cys(30) disulfides in alphaCT-alphaCT considerably potentiates inhibition of the alpha3beta2 nAChR by the toxin. The heteromeric dimer of alpha-cobratoxin and cytotoxin has an activity similar to that of alphaCT-alphaCT against the alpha7 nAChR and is more active against alpha3beta2 nAChRs. Our results demonstrate that at least one Cys(26)-Cys(30) disulfide in covalent TFT dimers, similar to the monomeric TFTs, is essential for their recognition by alpha7 nAChR, although it is less important for interaction of covalent TFT dimers with the alpha3beta2 nAChR.

Dimeric alpha-cobratoxin X-ray structure: localization of intermolecular disulfides and possible mode of binding to nicotinic acetylcholine receptors.,Osipov AV, Rucktooa P, Kasheverov IE, Filkin SY, Starkov VG, Andreeva TV, Sixma TK, Bertrand D, Utkin YN, Tsetlin VI J Biol Chem. 2012 Feb 24;287(9):6725-34. Epub 2012 Jan 5. PMID:22223648^[8]

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

References

↑ Osipov AV, Kasheverov IE, Makarova YV, Starkov VG, Vorontsova OV, Ziganshin RKh, Andreeva TV, Serebryakova MV, Benoit A, Hogg RC, Bertrand D, Tsetlin VI, Utkin YN. Naturally occurring disulfide-bound dimers of three-fingered toxins: a paradigm for biological activity diversification. J Biol Chem. 2008 May 23;283(21):14571-80. Epub 2008 Apr 1. PMID:18381281 doi:http://dx.doi.org/M802085200
↑ Osipov AV, Rucktooa P, Kasheverov IE, Filkin SY, Starkov VG, Andreeva TV, Sixma TK, Bertrand D, Utkin YN, Tsetlin VI. Dimeric alpha-cobratoxin X-ray structure: localization of intermolecular disulfides and possible mode of binding to nicotinic acetylcholine receptors. J Biol Chem. 2012 Feb 24;287(9):6725-34. Epub 2012 Jan 5. PMID:22223648 doi:10.1074/jbc.M111.322313
↑ Kudryavtsev DS, Shelukhina IV, Son LV, Ojomoko LO, Kryukova EV, Lyukmanova EN, Zhmak MN, Dolgikh DA, Ivanov IA, Kasheverov IE, Starkov VG, Ramerstorfer J, Sieghart W, Tsetlin VI, Utkin YN. Neurotoxins from snake venoms and α-conotoxin ImI inhibit functionally active ionotropic γ-aminobutyric acid (GABA) receptors. J Biol Chem. 2015 Sep 11;290(37):22747-58. PMID:26221036 doi:10.1074/jbc.M115.648824
↑ Yu J, Zhu X, Zhang L, Kudryavtsev D, Kasheverov I, Lei Y, Zhangsun D, Tsetlin V, Luo S. Species specificity of rat and human α7 nicotinic acetylcholine receptors towards different classes of peptide and protein antagonists. Neuropharmacology. 2018 Sep 1;139:226-237. PMID:30025921 doi:10.1016/j.neuropharm.2018.07.019
↑ Osipov AV, Kasheverov IE, Makarova YV, Starkov VG, Vorontsova OV, Ziganshin RKh, Andreeva TV, Serebryakova MV, Benoit A, Hogg RC, Bertrand D, Tsetlin VI, Utkin YN. Naturally occurring disulfide-bound dimers of three-fingered toxins: a paradigm for biological activity diversification. J Biol Chem. 2008 May 23;283(21):14571-80. Epub 2008 Apr 1. PMID:18381281 doi:http://dx.doi.org/M802085200
↑ Osipov AV, Rucktooa P, Kasheverov IE, Filkin SY, Starkov VG, Andreeva TV, Sixma TK, Bertrand D, Utkin YN, Tsetlin VI. Dimeric alpha-cobratoxin X-ray structure: localization of intermolecular disulfides and possible mode of binding to nicotinic acetylcholine receptors. J Biol Chem. 2012 Feb 24;287(9):6725-34. Epub 2012 Jan 5. PMID:22223648 doi:10.1074/jbc.M111.322313
↑ Osipov AV, Rucktooa P, Kasheverov IE, Filkin SY, Starkov VG, Andreeva TV, Sixma TK, Bertrand D, Utkin YN, Tsetlin VI. Dimeric alpha-cobratoxin X-ray structure: localization of intermolecular disulfides and possible mode of binding to nicotinic acetylcholine receptors. J Biol Chem. 2012 Feb 24;287(9):6725-34. Epub 2012 Jan 5. PMID:22223648 doi:10.1074/jbc.M111.322313
↑ Osipov AV, Rucktooa P, Kasheverov IE, Filkin SY, Starkov VG, Andreeva TV, Sixma TK, Bertrand D, Utkin YN, Tsetlin VI. Dimeric alpha-cobratoxin X-ray structure: localization of intermolecular disulfides and possible mode of binding to nicotinic acetylcholine receptors. J Biol Chem. 2012 Feb 24;287(9):6725-34. Epub 2012 Jan 5. PMID:22223648 doi:10.1074/jbc.M111.322313

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/4aea"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4aea]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Naja_kaouthia Naja kaouthia]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4AEA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4AEA FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GLY:GLYCINE'>GLY</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.94&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1lxh|1lxh]], [[1lxg|1lxg]], [[1ctx|1ctx]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GLY:GLYCINE'>GLY</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</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=4aea FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4aea OCA], [https://pdbe.org/4aea PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4aea RCSB], [https://www.ebi.ac.uk/pdbsum/4aea PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4aea ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/NXL1_NAJKA NXL1_NAJKA]] The monomeric form binds with high affinity to muscular, Torpedo (muscle-type), and neuronal alpha-7 nicotinic acetylcholine receptors (nAChR). Has no effect on alpha-3/beta-2 nAChR. Causes paralysis by preventing acetylcholine binding to the nAChR. Does not show any blockade of the nicotine-evoked release of dopamine and does not affect ACh release. In mice lung cancer, causes reduction of tumor growth.<ref>PMID:18381281</ref> <ref>PMID:6771288</ref> <ref>PMID:6553056</ref> <ref>PMID:2086254</ref> <ref>PMID:9053737</ref> <ref>PMID:9305882</ref> <ref>PMID:9840221</ref> <ref>PMID:10574958</ref> <ref>PMID:18067132</ref>   The homodimeric form binds with low affinity to Torpedo (muscle-type) and alpha-7 nAChRs, whereas it acquires the capacity to block alpha-3/beta-2 nAChRs.<ref>PMID:18381281</ref> <ref>PMID:6771288</ref> <ref>PMID:6553056</ref> <ref>PMID:2086254</ref> <ref>PMID:9053737</ref> <ref>PMID:9305882</ref> <ref>PMID:9840221</ref> <ref>PMID:10574958</ref> <ref>PMID:18067132</ref>
+[https://www.uniprot.org/uniprot/3L21_NAJKA 3L21_NAJKA] Monomer: binds with high affinity to muscular (alpha-1-beta-1-gamma-delta/CHRNA1-CHRNB1-CHRNG-CHRND) nAChR (tested on Torpedo californica, Kd=0.2-4.5 nM) and neuronal alpha-7/CHRNA7 nicotinic acetylcholine receptors (Kd=13-105 nM) (PubMed:18381281, PubMed:9305882, PubMed:22223648). Also inhibits GABA(A) channels (PubMed:26221036). Heteropentamer targets studied are composed of alpha-1-beta-3-gamma-2 (GABRA1-GABRB3-GABRG2) subunits (IC(50)=236 nM), alpha-1-beta-2-gamma-2 (GABRA1-GABRB2-GABRG2) subunits (IC(50)=469 nM), alpha-2-beta-2-gamma-2 (GABRA2-GABRB2-GABRG2) subunits (IC(50)=485 nM), alpha-5-beta-3-gamma-2 (GABRA5-GABRB3-GABRG2) subunits (IC(50)=635 nM), and alpha-2-beta-3-gamma-2 (GABRA2-GABRB3-GABRG2) subunits (IC(50)=1099 nM) (activated by 10 uM GABA) (PubMed:26221036).<ref>PMID:18381281</ref> <ref>PMID:22223648</ref> <ref>PMID:26221036</ref> <ref>PMID:30025921</ref>   Homodimer: binds with high affinity (but lower than the monomeric form) to muscular (IC(50)=9.7 nM) and with low affinity to neuronal alpha-7/CHRNA7 nAChRs (IC(50)=1370 nM) (PubMed:22223648). However, it acquires (compared to the monomeric form) the capacity to block alpha-3/beta-2 (CHRNA3/CHRNB2) nAChRs (PubMed:18381281).<ref>PMID:18381281</ref> <ref>PMID:22223648</ref>   Heterodimer with cytotoxin 3 (AC P01446): is slightly more active than the homodimer in inhibiting alpha-7/CHRNA7 nAChR and is considerably more active in blocking the alpha-3-beta-2/CHRNA3-CHRNB2 nAChR.<ref>PMID:22223648</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 25: / Line 25: @@
 [[Category: Large Structures]]
 [[Category: Naja kaouthia]]
-[[Category: Andreeva, T V]]
+[[Category: Andreeva TV]]
-[[Category: Bertrand, D]]
+[[Category: Bertrand D]]
-[[Category: Filkin, S Y]]
+[[Category: Filkin SY]]
-[[Category: Kasheverov, I E]]
+[[Category: Kasheverov IE]]
-[[Category: Osipov, A V]]
+[[Category: Osipov AV]]
-[[Category: Rucktooa, P]]
+[[Category: Rucktooa P]]
-[[Category: Sixma, T K]]
+[[Category: Sixma TK]]
-[[Category: Starkov, V G]]
+[[Category: Starkov VG]]
-[[Category: Tsetlin, V I]]
+[[Category: Tsetlin VI]]
-[[Category: Utkin, Y N]]
+[[Category: Utkin YN]]
-[[Category: Nicotinic acetylcholine receptor]]
-[[Category: Three-finger toxin]]
-[[Category: Toxin]]

4aea

From Proteopedia

Revision as of 11:24, 20 December 2023

Dimeric alpha-cobratoxin X-ray structure: Localization of intermolecular disulfides and possible mode of binding to nicotinic acetylcholine receptors

Structural highlights

Function

Publication Abstract from PubMed

References

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