6dik

From Proteopedia

(Difference between revisions)

Revision as of 06:07, 11 October 2023

Crystal structure of Bothropstoxin I (BthTX-I) complexed to Chicoric acid

Structural highlights

6dik is a 2 chain structure with sequence from Bothrops jararacussu. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.93Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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 (PubMed:27531710) (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 (PubMed:27531710) (By similarity). The MDoS region stabilizes the toxin on membrane by the interaction of charged residues with phospholipid head groups (PubMed:27531710) (By similarity). Subsequently, the MDiS region destabilizes the membrane with penetration of hydrophobic residues (PubMed:27531710) (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 (PubMed:27531710) (By similarity).[UniProtKB:I6L8L6]^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9]

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^[10]

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

References

↑ Andriao-Escarso SH, Soares AM, Rodrigues VM, Angulo Y, Diaz C, Lomonte B, Gutierrez JM, Giglio JR. Myotoxic phospholipases A(2) in bothrops snake venoms: effect of chemical modifications on the enzymatic and pharmacological properties of bothropstoxins from Bothrops jararacussu. Biochimie. 2000 Aug;82(8):755-63. PMID:11018293
↑ Ward RJ, Chioato L, de Oliveira AH, Ruller R, Sa JM. Active-site mutagenesis of a Lys49-phospholipase A2: biological and membrane-disrupting activities in the absence of catalysis. Biochem J. 2002 Feb 15;362(Pt 1):89-96. PMID:11829743
↑ Chioato L, De Oliveira AH, Ruller R, Sa JM, Ward RJ. Distinct sites for myotoxic and membrane-damaging activities in the C-terminal region of a Lys49-phospholipase A2. Biochem J. 2002 Sep 15;366(Pt 3):971-6. PMID:12079495 doi:http://dx.doi.org/10.1042/BJ20020092
↑ Murakami MT, Vicoti MM, Abrego JR, Lourenzoni MR, Cintra AC, Arruda EZ, Tomaz MA, Melo PA, Arni RK. Interfacial surface charge and free accessibility to the PLA2-active site-like region are essential requirements for the activity of Lys49 PLA2 homologues. Toxicon. 2007 Mar 1;49(3):378-87. Epub 2006 Nov 3. PMID:17157889 doi:10.1016/j.toxicon.2006.10.011
↑ Chioato L, Aragao EA, Lopes Ferreira T, Medeiros AI, Faccioli LH, Ward RJ. Mapping of the structural determinants of artificial and biological membrane damaging activities of a Lys49 phospholipase A2 by scanning alanine mutagenesis. Biochim Biophys Acta. 2007 May;1768(5):1247-57. Epub 2007 Feb 9. PMID:17346668 doi:http://dx.doi.org/10.1016/j.bbamem.2007.01.023
↑ Aragao EA, Chioato L, Ward RJ. Permeabilization of E. coli K12 inner and outer membranes by bothropstoxin-I, A LYS49 phospholipase A2 from Bothrops jararacussu. Toxicon. 2008 Mar 15;51(4):538-46. Epub 2007 Nov 17. PMID:18160090 doi:http://dx.doi.org/10.1016/j.toxicon.2007.11.004
↑ Borges RJ, Cardoso FF, Fernandes CA, Dreyer TR, de Moraes DS, Floriano RS, Rodrigues-Simioni L, Fontes MR. Functional and structural studies of a Phospholipase A2-like protein complexed to zinc ions: Insights on its myotoxicity and inhibition mechanism. Biochim Biophys Acta. 2017 Jan;1861(1 Pt A):3199-3209. doi:, 10.1016/j.bbagen.2016.08.003. Epub 2016 Aug 13. PMID:27531710 doi:http://dx.doi.org/10.1016/j.bbagen.2016.08.003
↑ Homsi-Brandeburgo MI, Queiroz LS, Santo-Neto H, Rodrigues-Simioni L, Giglio JR. Fractionation of Bothrops jararacussu snake venom: partial chemical characterization and biological activity of bothropstoxin. Toxicon. 1988;26(7):615-27. PMID:3176051
↑ Boeno CN, Paloschi MV, Lopes JA, Pires WL, Setubal SDS, Evangelista JR, Soares AM, Zuliani JP. Inflammasome Activation Induced by a Snake Venom Lys49-Phospholipase A2 Homologue. Toxins (Basel). 2019 Dec 31;12(1). pii: toxins12010022. doi:, 10.3390/toxins12010022. PMID:31906173 doi:http://dx.doi.org/10.3390/toxins12010022
↑ Cardoso FF, Borges RJ, Dreyer TR, Salvador GHM, Cavalcante WLG, Pai MD, Gallacci M, Fontes MRM. Structural basis of phospholipase A2-like myotoxin inhibition by chicoric acid, a novel potent inhibitor of ophidian toxins. 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 doi:http://dx.doi.org/10.1016/j.bbagen.2018.08.002

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6dik"

Categories: Bothrops jararacussu | Large Structures | Borges RJ | Cardoso FF | Salvador GHM

@@ Line 3: / Line 3: @@
 <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 [http://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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DIK FirstGlance]. <br>
+<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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BCT:BICARBONATE+ION'>BCT</scene>, <scene name='pdbligand=EOH:ETHANOL'>EOH</scene>, <scene name='pdbligand=GKP:(2R,3R)-2,3-bis{[(2E)-3-(3,4-dihydroxyphenyl)prop-2-enoyl]oxy}butanedioic+acid'>GKP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.93&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3iq3|3iq3]]</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:(2R,3R)-2,3-bis{[(2E)-3-(3,4-dihydroxyphenyl)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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6dik FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dik OCA], [http://pdbe.org/6dik PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dik RCSB], [http://www.ebi.ac.uk/pdbsum/6dik PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dik 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=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 ==
-[[http://www.uniprot.org/uniprot/PA2B1_BOTJR PA2B1_BOTJR]] Snake venom phospholipase A2 homolog that lacks enzymatic activity. In vivo, induces muscle necrosis, accompanied by polymorphonuclear cell infiltration, and edema in the mouse paw. Damages artificial and myoblast membranes by a calcium-independent mechanism. Has bactericidal activity.<ref>PMID:3176051</ref> <ref>PMID:11018293</ref> <ref>PMID:11829743</ref> <ref>PMID:12079495</ref> <ref>PMID:17346668</ref> <ref>PMID:18160090</ref> <ref>PMID:17157889</ref>
+[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 (PubMed:27531710) (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 (PubMed:27531710) (By similarity). The MDoS region stabilizes the toxin on membrane by the interaction of charged residues with phospholipid head groups (PubMed:27531710) (By similarity). Subsequently, the MDiS region destabilizes the membrane with penetration of hydrophobic residues (PubMed:27531710) (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 (PubMed:27531710) (By similarity).[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 ==
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 6dik" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Phospholipase A2 homolog|Phospholipase A2 homolog]]
 == References ==
 <references/>
@@ Line 25: / Line 28: @@
 [[Category: Bothrops jararacussu]]
 [[Category: Large Structures]]
-[[Category: Borges, R J]]
+[[Category: Borges RJ]]
-[[Category: Cardoso, F F]]
+[[Category: Cardoso FF]]
-[[Category: Salvador, G H.M]]
+[[Category: Salvador GHM]]
-[[Category: Bothropd jararacussu]]
-[[Category: Bthtx-i]]
-[[Category: Chicoric acid]]
-[[Category: Cichoric acid]]
-[[Category: Inhibitor]]
-[[Category: Pla2]]
-[[Category: Toxin]]

6dik

From Proteopedia

Revision as of 06:07, 11 October 2023

Crystal structure of Bothropstoxin I (BthTX-I) complexed to Chicoric acid

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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