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| | <StructureSection load='1y4l' size='340' side='right'caption='[[1y4l]], [[Resolution|resolution]] 1.70Å' scene=''> | | <StructureSection load='1y4l' size='340' side='right'caption='[[1y4l]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1y4l]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Botas Botas]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Y4L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1Y4L FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1y4l]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bothrops_asper Bothrops asper]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Y4L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1Y4L FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=P33:3,6,9,12,15,18-HEXAOXAICOSANE-1,20-DIOL'>P33</scene>, <scene name='pdbligand=SVR:8,8-[CARBONYLBIS[IMINO-3,1-PHENYLENECARBONYLIMINO(4-METHYL-3,1-PHENYLENE)CARBONYLIMINO]]BIS-1,3,5-NAPHTHALENETRISULFONIC+ACID'>SVR</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]] 1.7Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1clp|1clp]]</div></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=P33:3,6,9,12,15,18-HEXAOXAICOSANE-1,20-DIOL'>P33</scene>, <scene name='pdbligand=SVR:8,8-[CARBONYLBIS[IMINO-3,1-PHENYLENECARBONYLIMINO(4-METHYL-3,1-PHENYLENE)CARBONYLIMINO]]BIS-1,3,5-NAPHTHALENETRISULFONIC+ACID'>SVR</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Phospholipase_A(2) Phospholipase A(2)], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.4 3.1.1.4] </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=1y4l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1y4l OCA], [https://pdbe.org/1y4l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1y4l RCSB], [https://www.ebi.ac.uk/pdbsum/1y4l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1y4l 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=1y4l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1y4l OCA], [https://pdbe.org/1y4l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1y4l RCSB], [https://www.ebi.ac.uk/pdbsum/1y4l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1y4l ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/PA2H2_BOTAS PA2H2_BOTAS] Snake venom phospholipase A2 homolog that lacks enzymatic activity. Is myotoxic and induces a dose-dependent edema in the mouse foot pad (PubMed:2781572, PubMed:9839670). Also exhibits strong anticoagulant effects by binding to factor Xa (F10) and inhibiting the prothrombinase activity (IC(50) is 3 nM) (PubMed:18062812). In addition, it shows cytotoxic activity to a variety of cell types and bactericidal activity to a variety of Gram-negative and Gram-positive bacteria (PubMed:7886694, PubMed:9654096, PubMed:9920486). Also induces a very rapid release of large amounts of potassium ions and ATP from muscle cells, which accounts for the pain reaction characteristic of viperid envenomations (PubMed:20660736). The released ATP amplifies the effect of the myotoxins, acting as a 'danger signal', which spreads and causes further damage by acting on purinergic receptors (PubMed:20660736). A model of myotoxic mechanism has been proposed: an apo Lys49-PLA2 is activated by the entrance of a hydrophobic molecule (e.g. fatty acid) at the hydrophobic channel of the protein leading to a reorientation of a monomer (By similarity). This reorientation causes a transition between 'inactive' to 'active' states, causing alignment of C-terminal and membrane-docking sites (MDoS) side-by-side and putting the membrane-disruption sites (MDiS) in the same plane, exposed to solvent and in a symmetric position for both monomers (By similarity). The MDoS region stabilizes the toxin on membrane by the interaction of charged residues with phospholipid head groups (By similarity). Subsequently, the MDiS region destabilizes the membrane with penetration of hydrophobic residues (By similarity). This insertion causes a disorganization of the membrane, allowing an uncontrolled influx of ions (i.e. calcium and sodium), and eventually triggering irreversible intracellular alterations and cell death (By similarity).[UniProtKB:I6L8L6]<ref>PMID:18062812</ref> <ref>PMID:1899180</ref> <ref>PMID:20660736</ref> <ref>PMID:2781572</ref> <ref>PMID:7886694</ref> <ref>PMID:9654096</ref> <ref>PMID:9839670</ref> <ref>PMID:9920486</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Botas]] | + | [[Category: Bothrops asper]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Arni, R K]] | + | [[Category: Arni RK]] |
| - | [[Category: Arruda, E Z]] | + | [[Category: Arruda EZ]] |
| - | [[Category: Calil-Elias, S]] | + | [[Category: Calil-Elias S]] |
| - | [[Category: Gutierrez, J M]] | + | [[Category: Gutierrez JM]] |
| - | [[Category: Lomonte, B]] | + | [[Category: Lomonte B]] |
| - | [[Category: Martinez, A B]] | + | [[Category: Martinez AB]] |
| - | [[Category: Melo, P A]] | + | [[Category: Melo PA]] |
| - | [[Category: Murakami, M T]] | + | [[Category: Murakami MT]] |
| - | [[Category: Tomaz, M A]] | + | [[Category: Tomaz MA]] |
| - | [[Category: Anti-trypanosomal drug suramin]]
| + | |
| - | [[Category: Bothrops asper myotoxin ii]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| Structural highlights
Function
PA2H2_BOTAS Snake venom phospholipase A2 homolog that lacks enzymatic activity. Is myotoxic and induces a dose-dependent edema in the mouse foot pad (PubMed:2781572, PubMed:9839670). Also exhibits strong anticoagulant effects by binding to factor Xa (F10) and inhibiting the prothrombinase activity (IC(50) is 3 nM) (PubMed:18062812). In addition, it shows cytotoxic activity to a variety of cell types and bactericidal activity to a variety of Gram-negative and Gram-positive bacteria (PubMed:7886694, PubMed:9654096, PubMed:9920486). Also induces a very rapid release of large amounts of potassium ions and ATP from muscle cells, which accounts for the pain reaction characteristic of viperid envenomations (PubMed:20660736). The released ATP amplifies the effect of the myotoxins, acting as a 'danger signal', which spreads and causes further damage by acting on purinergic receptors (PubMed:20660736). A model of myotoxic mechanism has been proposed: an apo Lys49-PLA2 is activated by the entrance of a hydrophobic molecule (e.g. fatty acid) at the hydrophobic channel of the protein leading to a reorientation of a monomer (By similarity). This reorientation causes a transition between 'inactive' to 'active' states, causing alignment of C-terminal and membrane-docking sites (MDoS) side-by-side and putting the membrane-disruption sites (MDiS) in the same plane, exposed to solvent and in a symmetric position for both monomers (By similarity). The MDoS region stabilizes the toxin on membrane by the interaction of charged residues with phospholipid head groups (By similarity). Subsequently, the MDiS region destabilizes the membrane with penetration of hydrophobic residues (By similarity). This insertion causes a disorganization of the membrane, allowing an uncontrolled influx of ions (i.e. calcium and sodium), and eventually triggering irreversible intracellular alterations and cell death (By similarity).[UniProtKB:I6L8L6][1] [2] [3] [4] [5] [6] [7] [8]
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
Suramin, a synthetic polysulfonated compound, developed initially for the treatment of African trypanosomiasis and onchocerciasis, is currently used for the treatment of several medically relevant disorders. Suramin, heparin, and other polyanions inhibit the myotoxic activity of Lys49 phospholipase A2 analogues both in vitro and in vivo, and are thus of potential importance as therapeutic agents in the treatment of viperid snake bites. Due to its conformational flexibility around the single bonds that link the central phenyl rings to the secondary amide backbone, the symmetrical suramin molecule binds by an induced-fit mechanism complementing the hydrophobic surfaces of the dimer and adopts a novel conformation that lacks C2 symmetry in the dimeric crystal structure of the suramin-Bothrops asper myotoxin II complex. The simultaneous binding of suramin at the surfaces of the two monomers partially restricts access to the nominal active sites and significantly changes the overall charge of the interfacial recognition face of the protein, resulting in the inhibition of myotoxicity.
Inhibition of myotoxic activity of Bothrops asper myotoxin II by the anti-trypanosomal drug suramin.,Murakami MT, Arruda EZ, Melo PA, Martinez AB, Calil-Elias S, Tomaz MA, Lomonte B, Gutierrez JM, Arni RK J Mol Biol. 2005 Jul 15;350(3):416-26. PMID:15961104[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Faure G, Gowda VT, Maroun RC. Characterization of a human coagulation factor Xa-binding site on Viperidae snake venom phospholipases A2 by affinity binding studies and molecular bioinformatics. BMC Struct Biol. 2007 Dec 6;7:82. PMID:18062812 doi:http://dx.doi.org/10.1186/1472-6807-7-82
- ↑ Francis B, Gutierrez JM, Lomonte B, Kaiser II. Myotoxin II from Bothrops asper (Terciopelo) venom is a lysine-49 phospholipase A2. Arch Biochem Biophys. 1991 Feb 1;284(2):352-9. PMID:1899180 doi:10.1016/0003-9861(91)90307-5
- ↑ Cintra-Francischinelli M, Caccin P, Chiavegato A, Pizzo P, Carmignoto G, Angulo Y, Lomonte B, Gutiérrez JM, Montecucco C. Bothrops snake myotoxins induce a large efflux of ATP and potassium with spreading of cell damage and pain. Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14140-5. PMID:20660736 doi:10.1073/pnas.1009128107
- ↑ Lomonte B, Gutiérrez JM. A new muscle damaging toxin, myotoxin II, from the venom of the snake Bothrops asper (terciopelo). Toxicon. 1989;27(7):725-33. PMID:2781572 doi:10.1016/0041-0101(89)90039-1
- ↑ Lomonte B, Tarkowski A, Hanson LA. Broad cytolytic specificity of myotoxin II, a lysine-49 phospholipase A2 of Bothrops asper snake venom. Toxicon. 1994 Nov;32(11):1359-69. PMID:7886694 doi:10.1016/0041-0101(94)90408-1
- ↑ Páramo L, Lomonte B, Pizarro-Cerdá J, Bengoechea JA, Gorvel JP, Moreno E. Bactericidal activity of Lys49 and Asp49 myotoxic phospholipases A2 from Bothrops asper snake venom--synthetic Lys49 myotoxin II-(115-129)-peptide identifies its bactericidal region. Eur J Biochem. 1998 Apr 15;253(2):452-61. PMID:9654096 doi:10.1046/j.1432-1327.1998.2530452.x
- ↑ Chaves F, Leon G, Alvarado VH, Gutierrez JM. Pharmacological modulation of edema induced by Lys-49 and Asp-49 myotoxic phospholipases A2 isolated from the venom of the snake Bothrops asper (terciopelo). Toxicon. 1998 Dec;36(12):1861-9. PMID:9839670
- ↑ Lomonte B, Angulo Y, Rufini S, Cho W, Giglio JR, Ohno M, Daniele JJ, Geoghegan P, Gutiérrez JM. Comparative study of the cytolytic activity of myotoxic phospholipases A2 on mouse endothelial (tEnd) and skeletal muscle (C2C12) cells in vitro. Toxicon. 1999 Jan;37(1):145-58. PMID:9920486 doi:10.1016/s0041-0101(98)00171-8
- ↑ Murakami MT, Arruda EZ, Melo PA, Martinez AB, Calil-Elias S, Tomaz MA, Lomonte B, Gutierrez JM, Arni RK. Inhibition of myotoxic activity of Bothrops asper myotoxin II by the anti-trypanosomal drug suramin. J Mol Biol. 2005 Jul 15;350(3):416-26. PMID:15961104 doi:http://dx.doi.org/10.1016/j.jmb.2005.04.072
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