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1xt3

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Structure Basis of Venom Citrate-Dependent Heparin Sulfate-Mediated Cell Surface Retention of Cobra Cardiotoxin A3

Structural highlights

1xt3 is a 2 chain structure with sequence from Naja atra. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.4Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

3SA3_NAJAT Basic protein that binds to cell membrane and depolarizes cardiomyocytes. This cytotoxin also possesses lytic activity on many other cells, including red blood cells (PubMed:8182052). Interaction with sulfatides in the cell membrane induces pore formation and cell internalization. Cytotoxicity is due to pore formation, and to another mechanism independent of membrane-damaging activity. When internalized, it targets the mitochondrial membrane and induces mitochondrial swelling and fragmentation. It inhibits protein kinases C. It binds to the integrin alpha-V/beta-3 (ITGAV/ITGB3) with a moderate affinity (PubMed:16407244). It also binds with high affinity to heparin (PubMed:17685633).^[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

Anionic citrate is a major component of venom, but the role of venom citrate in toxicity other than its inhibitory effect on the cation-dependent action of venom toxins is poorly understood. By immobilizing Chinese hamster ovary cells in microcapillary tubes and heparin on sensor chips, we demonstrated that heparan sulfate-mediated cell retention of the major cardiotoxin (CTX) from the Taiwan cobra, CTX A3, near membrane surfaces is citrate-dependent. X-ray determination of a CTX A3-heparin hexasaccharide complex structure at 2.4 A resolution revealed a molecular mechanism for toxin retention in which heparin-induced conformational changes of CTX A3 lead to citrate-mediated dimerization. A citrate ion bound to Lys-23 and Lys-31 near the tip of loop II stabilizes hydrophobic contact of the CTX A3 homodimer at the functionally important loop I and II regions. Additionally, the heparin hexasaccharide interacts with five CTX A3 molecules in the crystal structure, providing another mechanism whereby the toxin establishes a complex network of interactions that result in a strong interaction with cell surfaces presenting heparan sulfate. Our results suggest a novel role for venom citrate in biological activity and reveal a structural model that explains cell retention of cobra CTX A3 through heparan sulfate-CTX interactions.

Structural basis of citrate-dependent and heparan sulfate-mediated cell surface retention of cobra cardiotoxin A3.,Lee SC, Guan HH, Wang CH, Huang WN, Tjong SC, Chen CJ, Wu WG J Biol Chem. 2005 Mar 11;280(10):9567-77. Epub 2004 Dec 6. PMID:15590643^[8]

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

References

↑ Wang CH, Wu WG. Amphiphilic beta-sheet cobra cardiotoxin targets mitochondria and disrupts its network. FEBS Lett. 2005 Jun 6;579(14):3169-74. PMID:15922335 doi:http://dx.doi.org/S0014-5793(05)00579-X
↑ Wang CH, Liu JH, Lee SC, Hsiao CD, Wu WG. Glycosphingolipid-facilitated membrane insertion and internalization of cobra cardiotoxin. The sulfatide.cardiotoxin complex structure in a membrane-like environment suggests a lipid-dependent cell-penetrating mechanism for membrane binding polypeptides. J Biol Chem. 2006 Jan 6;281(1):656-67. Epub 2005 Nov 1. PMID:16263708 doi:10.1074/jbc.M507880200
↑ Wu PL, Lee SC, Chuang CC, Mori S, Akakura N, Wu WG, Takada Y. Non-cytotoxic cobra cardiotoxin A5 binds to alpha(v)beta3 integrin and inhibits bone resorption. Identification of cardiotoxins as non-RGD integrin-binding proteins of the Ly-6 family. J Biol Chem. 2006 Mar 24;281(12):7937-45. Epub 2006 Jan 10. PMID:16407244 doi:http://dx.doi.org/M513035200
↑ Chen KC, Kao PH, Lin SR, Chang LS. The mechanism of cytotoxicity by Naja naja atra cardiotoxin 3 is physically distant from its membrane-damaging effect. Toxicon. 2007 Nov;50(6):816-24. Epub 2007 Jun 27. PMID:17714752 doi:http://dx.doi.org/S0041-0101(07)00224-3
↑ Chien KY, Chiang CM, Hseu YC, Vyas AA, Rule GS, Wu W. Two distinct types of cardiotoxin as revealed by the structure and activity relationship of their interaction with zwitterionic phospholipid dispersions. J Biol Chem. 1994 May 20;269(20):14473-83. PMID:8182052
↑ Chiou SH, Raynor RL, Zheng B, Chambers TC, Kuo JF. Cobra venom cardiotoxin (cytotoxin) isoforms and neurotoxin: comparative potency of protein kinase C inhibition and cancer cell cytotoxicity and modes of enzyme inhibition. Biochemistry. 1993 Mar 2;32(8):2062-7. PMID:8448165
↑ Sue SC, Rajan PK, Chen TS, Hsieh CH, Wu W. Action of Taiwan cobra cardiotoxin on membranes: binding modes of a beta-sheet polypeptide with phosphatidylcholine bilayers. Biochemistry. 1997 Aug 12;36(32):9826-36. PMID:9245415 doi:http://dx.doi.org/10.1021/bi970413l
↑ Lee SC, Guan HH, Wang CH, Huang WN, Tjong SC, Chen CJ, Wu WG. Structural basis of citrate-dependent and heparan sulfate-mediated cell surface retention of cobra cardiotoxin A3. J Biol Chem. 2005 Mar 11;280(10):9567-77. Epub 2004 Dec 6. PMID:15590643 doi:10.1074/jbc.M412398200

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1xt3"

@@ Line 1: / Line 1: @@
 ==Structure Basis of Venom Citrate-Dependent Heparin Sulfate-Mediated Cell Surface Retention of Cobra Cardiotoxin A3==
-<StructureSection load='1xt3' size='340' side='right' caption='[[1xt3]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
+<StructureSection load='1xt3' size='340' side='right'caption='[[1xt3]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1xt3]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Naja_atra Naja atra]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XT3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1XT3 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1xt3]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Naja_atra Naja atra]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XT3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1XT3 FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=IDS:2-O-SULFO-ALPHA-L-IDOPYRANURONIC+ACID'>IDS</scene>, <scene name='pdbligand=SGN:N,O6-DISULFO-GLUCOSAMINE'>SGN</scene><br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4&#8491;</td></tr>
-<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1xt3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xt3 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1xt3 RCSB], [http://www.ebi.ac.uk/pdbsum/1xt3 PDBsum]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=IDS:2-O-SULFO-ALPHA-L-IDOPYRANURONIC+ACID'>IDS</scene>, <scene name='pdbligand=SGN:N,O6-DISULFO-GLUCOSAMINE'>SGN</scene></td></tr>
-<table>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1xt3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xt3 OCA], [https://pdbe.org/1xt3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1xt3 RCSB], [https://www.ebi.ac.uk/pdbsum/1xt3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1xt3 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/3SA3_NAJAT 3SA3_NAJAT] Basic protein that binds to cell membrane and depolarizes cardiomyocytes. This cytotoxin also possesses lytic activity on many other cells, including red blood cells (PubMed:8182052). Interaction with sulfatides in the cell membrane induces pore formation and cell internalization. Cytotoxicity is due to pore formation, and to another mechanism independent of membrane-damaging activity. When internalized, it targets the mitochondrial membrane and induces mitochondrial swelling and fragmentation. It inhibits protein kinases C. It binds to the integrin alpha-V/beta-3 (ITGAV/ITGB3) with a moderate affinity (PubMed:16407244). It also binds with high affinity to heparin (PubMed:17685633).<ref>PMID:15922335</ref> <ref>PMID:16263708</ref> <ref>PMID:16407244</ref> <ref>PMID:17714752</ref> <ref>PMID:8182052</ref> <ref>PMID:8448165</ref> <ref>PMID:9245415</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/xt/1xt3_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/xt/1xt3_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.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/chain_selection.php?pdb_ID=2ata 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=1xt3 ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 24: / Line 28: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 1xt3" style="background-color:#fffaf0;"></div>
 ==See Also==
-*[[Cardiotoxin|Cardiotoxin]]
+*[[Cardiotoxin 3D structures|Cardiotoxin 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Naja atra]]
-[[Category: Chen, C J.]]
+[[Category: Chen C-J]]
-[[Category: Guan, H H.]]
+[[Category: Guan H-H]]
-[[Category: Huang, W N.]]
+[[Category: Huang W-N]]
-[[Category: Lee, S C.]]
+[[Category: Lee S-C]]
-[[Category: Wang, C H.]]
+[[Category: Wang C-H]]
-[[Category: Wu, W G.]]
+[[Category: Wu W-G]]
-[[Category: Citrate]]
-[[Category: Ctx-3]]
-[[Category: Heparin]]
-[[Category: Toxin]]

1xt3

From Proteopedia

Current revision

Structure Basis of Venom Citrate-Dependent Heparin Sulfate-Mediated Cell Surface Retention of Cobra Cardiotoxin A3

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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