View source for 6dik


==Crystal structure of Bothropstoxin I (BthTX-I) complexed to Chicoric acid==
<StructureSection load='6dik' size='340' side='right'caption='[[6dik]], [[Resolution|resolution]] 1.93&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6dik]] 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=6DIK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DIK FirstGlance]. <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]] 1.93&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BCT:BICARBONATE+ION'>BCT</scene>, <scene name='pdbligand=EOH:ETHANOL'>EOH</scene>, <scene name='pdbligand=GKP:(2~{R},3~{R})-2,3-bis[[(~{E})-3-[3,4-bis(oxidanyl)phenyl]prop-2-enoyl]oxy]butanedioic+acid'>GKP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6dik FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dik OCA], [https://pdbe.org/6dik PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dik RCSB], [https://www.ebi.ac.uk/pdbsum/6dik PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dik ProSAT]</span></td></tr>
</table>
== Function ==
[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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
BACKGROUND: Specific compounds found in vegetal species have been demonstrated to be efficient inhibitors of snake toxins, such as phospholipase A2-like (PLA2-like) proteins. These particular proteins, present in several species of vipers (Viperidae), induce a severe local myotoxic effect in prey and human victims, and this effect is often not efficiently neutralized by the regular serum therapy. PLA2-like proteins have been functionally and structurally studied since the early 1990s; however, a comprehensive molecular mechanism was proposed only recently. METHODS: Myographic and histological techniques were used to evaluate the inhibitory effect of chicoric acid (CA) against BthTX-I myotoxin. Isothermal titration calorimetry assays were used to measure the affinity between the inhibitor and the toxin. X-ray crystallography was used to reveal details of this interaction. RESULTS: CA prevented the blockade of indirectly evoked muscle contraction and inhibited muscle damage induced by BthTX-I. The inhibitor binds to the toxin with the highest affinity measured for a natural compound in calorimetric assays. The crystal structure and molecular dynamics simulations demonstrated that CA binds at the entrance of the hydrophobic channel of the toxin and binds to one of the clusters that participates in membrane disruption. CONCLUSIONS: CA prevents the myotoxic activity of the toxin, preventing its activation by simultaneous binding with two critical regions. GENERAL SIGNIFICANCE: CA is a potential myotoxic inhibitor to other PLA2-like proteins and a possible candidate to complement serum therapy.

Structural basis of phospholipase A2-like myotoxin inhibition by chicoric acid, a novel potent inhibitor of ophidian toxins.,Cardoso FF, Borges RJ, Dreyer TR, Salvador GHM, Cavalcante WLG, Pai MD, Gallacci M, Fontes MRM Biochim Biophys Acta Gen Subj. 2018 Dec;1862(12):2728-2737. doi:, 10.1016/j.bbagen.2018.08.002. Epub 2018 Aug 4. PMID:30251662<ref>PMID:30251662</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6dik" style="background-color:#fffaf0;"></div>

==See Also==
*[[Phospholipase A2 homolog|Phospholipase A2 homolog]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Bothrops jararacussu]]
[[Category: Large Structures]]
[[Category: Borges RJ]]
[[Category: Cardoso FF]]
[[Category: Salvador GHM]]