2h8i

From Proteopedia

(Difference between revisions)

Revision as of 09:58, 21 December 2022

Crystal Structure of the Bothropstoxin-I complexed with polyethylene glycol

Structural highlights

2h8i 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.
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]

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

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.

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^[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
↑ 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

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2h8i"

Categories: Bothrops jararacussu | Large Structures | Arni RK | Murakami MT

@@ Line 3: / Line 3: @@
 <StructureSection load='2h8i' size='340' side='right'caption='[[2h8i]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2h8i]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Botjr Botjr]. 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>
+<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>
 </td></tr><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>
 <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>
 </table>
 == Function ==
-[[https://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>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 36: / Line 36: @@
 __TOC__
 </StructureSection>
-[[Category: Botjr]]
+[[Category: Bothrops jararacussu]]
 [[Category: Large Structures]]
-[[Category: Arni, R K]]
+[[Category: Arni RK]]
-[[Category: Murakami, M T]]
+[[Category: Murakami MT]]
-[[Category: Lys49-pla2]]
-[[Category: Myotoxicity]]
-[[Category: Toxin]]

2h8i

From Proteopedia

Revision as of 09:58, 21 December 2022

Crystal Structure of the Bothropstoxin-I complexed with polyethylene glycol

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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