2h8i

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[[Image:2h8i.png|left|200px]]
 
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{{STRUCTURE_2h8i| PDB=2h8i | SCENE= }}
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==Crystal Structure of the Bothropstoxin-I complexed with polyethylene glycol==
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<StructureSection load='2h8i' size='340' side='right'caption='[[2h8i]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2h8i]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bothrops_jararacussu Bothrops jararacussu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H8I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2H8I FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2h8i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2h8i OCA], [https://pdbe.org/2h8i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2h8i RCSB], [https://www.ebi.ac.uk/pdbsum/2h8i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2h8i ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/PA2H1_BOTJR PA2H1_BOTJR] Snake venom phospholipase A2 homolog that lacks enzymatic activity. Shows local myotoxic activity (PubMed:11018293, PubMed:12079495, PubMed:31906173). Induces inflammation, since it induces edema and leukocytes infiltration (PubMed:11018293, PubMed:31906173). In addition, it induces NLRP3 NLRP3, ASC (PYCARD), caspase-1 (CASP1), and IL-1beta (IL1B) gene expression in the gastrocnemius muscle, showing that it is able to activate NLRP3 inflammasome (PubMed:31906173). It also damages artificial and myoblast membranes by a calcium-independent mechanism, has bactericidal activity, and induces neuromuscular blockade (PubMed:27531710). 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) (PubMed:27531710). 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) (PubMed:27531710). The MDoS region stabilizes the toxin on membrane by the interaction of charged residues with phospholipid head groups (By similarity) (PubMed:27531710). Subsequently, the MDiS region destabilizes the membrane with penetration of hydrophobic residues (By similarity) (PubMed:27531710). 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) (PubMed:27531710).[UniProtKB:I6L8L6]<ref>PMID:11018293</ref> <ref>PMID:11829743</ref> <ref>PMID:12079495</ref> <ref>PMID:17157889</ref> <ref>PMID:17346668</ref> <ref>PMID:18160090</ref> <ref>PMID:27531710</ref> <ref>PMID:3176051</ref> <ref>PMID:31906173</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/h8/2h8i_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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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=2h8i ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Lys49 phospholipase A2 homologues are highly myotoxic and cause extensive tissue damage but do not display hydrolytic activity towards natural phospholipids. The binding of heparin, heparin derivatives and polyanionic compounds such as suramin result in partial inhibition (up to 60%) of the myotoxic effects due to a change in the overall charge of the interfacial surface. In vivo experiments demonstrate that polyethylene glycol inhibits more than 90% of the myotoxic effects without exhibiting secondary toxic effects. The crystal structure of bothropstoxin-I complexed with polyethylene glycol reveals that this inhibition is due to steric hindrance of the access to the PLA2-active site-like region. These two inhibitory pathways indicate the roles of the overall surface charge and free accessibility to the PLA2-active site-like region in the functioning of Lys49 phospholipases A2 homologues. Molecular dynamics simulations, small angle X-ray scattering and structural analysis indicate that the oligomeric states both in solution and in the crystalline states of Lys49 phospholipases A2 are principally mediated by hydrophobic contacts formed between the interfacial surfaces. These results provide the framework for the potential application of both clinically approved drugs for the treatment of Viperidae snakebites.
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===Crystal Structure of the Bothropstoxin-I complexed with polyethylene glycol===
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Interfacial surface charge and free accessibility to the PLA2-active site-like region are essential requirements for the activity of Lys49 PLA2 homologues.,Murakami MT, Vicoti MM, Abrego JR, Lourenzoni MR, Cintra AC, Arruda EZ, Tomaz MA, Melo PA, Arni RK Toxicon. 2007 Mar 1;49(3):378-87. Epub 2006 Nov 3. PMID:17157889<ref>PMID:17157889</ref>
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{{ABSTRACT_PUBMED_17157889}}
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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==About this Structure==
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<div class="pdbe-citations 2h8i" style="background-color:#fffaf0;"></div>
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[[2h8i]] is a 2 chain structure of [[Phospholipase A2]] with sequence from [http://en.wikipedia.org/wiki/Bothrops_jararacussu Bothrops jararacussu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H8I OCA].
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==See Also==
==See Also==
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*[[Phospholipase A2|Phospholipase A2]]
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*[[Phospholipase A2 3D structures|Phospholipase A2 3D structures]]
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*[[Phospholipase A2 homolog|Phospholipase A2 homolog]]
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==Reference==
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== References ==
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<ref group="xtra">PMID:017157889</ref><references group="xtra"/>
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<references/>
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__TOC__
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</StructureSection>
[[Category: Bothrops jararacussu]]
[[Category: Bothrops jararacussu]]
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[[Category: Arni, R K.]]
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[[Category: Large Structures]]
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[[Category: Murakami, M T.]]
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[[Category: Arni RK]]
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[[Category: Lys49-pla2]]
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[[Category: Murakami MT]]
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[[Category: Myotoxicity]]
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[[Category: Toxin]]
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Current revision

Crystal Structure of the Bothropstoxin-I complexed with polyethylene glycol

PDB ID 2h8i

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