3i03

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[[Image:3i03.png|left|200px]]
 
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{{STRUCTURE_3i03| PDB=3i03 | SCENE= }}
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==Crystal structure of bothropstoxin-I chemically modified by p-bromophenacyl bromide (BPB) - monomeric form at a high resolution==
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<StructureSection load='3i03' size='340' side='right'caption='[[3i03]], [[Resolution|resolution]] 1.48&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3i03]] is a 1 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=3I03 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3I03 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]] 1.48&#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=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=PBP:1-(4-BROMO-PHENYL)-ETHANONE'>PBP</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=3i03 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3i03 OCA], [https://pdbe.org/3i03 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3i03 RCSB], [https://www.ebi.ac.uk/pdbsum/3i03 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3i03 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/i0/3i03_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=3i03 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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Phospholipases A(2) (Asp49-PLA(2)s) are enzymes responsible for cellular membrane disruption through Ca(2+)-dependent hydrolysis of phospholipids. A class of these proteins (Lys49-PLA(2)s) does not show catalytic activity but can exert a pronounced local myotoxic effect that is not neutralized by serum therapy. In this work, we present five structures of Lys49-PLA(2)s from snakes of the Bothrops genus in apo form, complexed with PEG molecules and chemically modified by p-bromofenacil bromide (BPB), a classic inhibitor of PLA(2). We present herein an extensive structural analysis including: (i) the function of hydrophobic long-chain molecules as Lys49-PLA(2)s inhibitors, (ii) the role of Lys122, previously indicated as being responsible for Lys49-PLA(2)s catalytic inactivity and, (iii) a structural comparison of the Ca(2+)-binding loop region between Lys49 and Asp49-PLA(2)s. The Lys122 analysis of 30 different monomers for apo and complexed Lys49-PLA(2)s structures shows that this residue is very flexible and may bind to different carboxyl groups giving stability to the crystal structures. The structural comparisons of the Ca(2+)-binding loop region between Lys49 and Asp49-PLA(2)s reveal the importance of the Tyr28 residue conservation in Asp49-PLA(2)s to the integrity of this loop. The Tyr28 residue stabilizes this region by an interaction with Gly35 residue. In Lys49-PLA(2)s and low-catalytic Asp49-PLA(2)s this interaction does not occur, preventing the binding of Ca(2+).
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===Crystal structure of bothropstoxin-I chemically modified by p-bromophenacyl bromide (BPB) - monomeric form at a high resolution===
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Comparison between apo and complexed structures of bothropstoxin-I reveals the role of Lys122 and Ca(2+)-binding loop region for the catalytically inactive Lys49-PLA(2)s.,Fernandes CA, Marchi-Salvador DP, Salvador GM, Silva MC, Costa TR, Soares AM, Fontes MR J Struct Biol. 2010 Apr 4. PMID:20371382<ref>PMID:20371382</ref>
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{{ABSTRACT_PUBMED_20371382}}
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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 3i03" style="background-color:#fffaf0;"></div>
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[[3i03]] is a 1 chain structure 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=3I03 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:020371382</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: Fernandes, C A.H.]]
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[[Category: Large Structures]]
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[[Category: Fontes, M R.M.]]
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[[Category: Fernandes CAH]]
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[[Category: Marchi-Salvador, D P.]]
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[[Category: Fontes MRM]]
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[[Category: Soares, A M.]]
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[[Category: Marchi-Salvador DP]]
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[[Category: Antibiotic]]
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[[Category: Soares AM]]
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[[Category: Antimicrobial]]
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[[Category: Bothropstoxin-i]]
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[[Category: Disulfide bond]]
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[[Category: Lys49-pla2]]
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[[Category: Myotoxicity]]
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[[Category: Myotoxin]]
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[[Category: P-bromophenacyl bromide]]
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[[Category: Phospholipase homologue]]
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[[Category: Secreted]]
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[[Category: Toxin]]
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Current revision

Crystal structure of bothropstoxin-I chemically modified by p-bromophenacyl bromide (BPB) - monomeric form at a high resolution

PDB ID 3i03

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