4dcf: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4dcf]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Bothrops_brazili Bothrops brazili]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DCF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DCF FirstGlance]. <br>
<table><tr><td colspan='2'>[[4dcf]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Bothrops_brazili Bothrops brazili]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DCF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DCF FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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]] 2.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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=4dcf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dcf OCA], [https://pdbe.org/4dcf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dcf RCSB], [https://www.ebi.ac.uk/pdbsum/4dcf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dcf 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=4dcf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dcf OCA], [https://pdbe.org/4dcf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dcf RCSB], [https://www.ebi.ac.uk/pdbsum/4dcf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dcf ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[https://www.uniprot.org/uniprot/PA2H1_BOTBZ PA2H1_BOTBZ]] Snake venom phospholipase A2 homolog that lacks enzymatic activity. Is myotoxic and displays edema-inducing activities in mouse paw (PubMed:18602430). Also displays cytotoxic activity against some cell lines, and antimicrobial activities against E.coli, C.albicans and Leishmania (PubMed:18602430). 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:24145104). 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:24145104). The MDoS region stabilizes the toxin on membrane by the interaction of charged residues with phospholipid head groups (PubMed:24145104). Subsequently, the MDiS region destabilizes the membrane with penetration of hydrophobic residues (PubMed:24145104). 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:24145104).<ref>PMID:18602430</ref> <ref>PMID:24145104</ref>
[https://www.uniprot.org/uniprot/PA2H1_BOTBZ PA2H1_BOTBZ] Snake venom phospholipase A2 homolog that lacks enzymatic activity. Is myotoxic and displays edema-inducing activities in mouse paw (PubMed:18602430). Also displays cytotoxic activity against some cell lines, and antimicrobial activities against E.coli, C.albicans and Leishmania (PubMed:18602430). 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:24145104). 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:24145104). The MDoS region stabilizes the toxin on membrane by the interaction of charged residues with phospholipid head groups (PubMed:24145104). Subsequently, the MDiS region destabilizes the membrane with penetration of hydrophobic residues (PubMed:24145104). 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:24145104).<ref>PMID:18602430</ref> <ref>PMID:24145104</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Catalytically inactive phospholipase A(2) (PLA(2)) homologues play key roles in the pathogenesis induced by snake envenomation, causing extensive tissue damage via a mechanism still unknown. Although, the amino acid residues directly involved in catalysis are conserved, the substitution of Asp49 by Arg/Lys/Gln or Ser prevents the binding of the essential calcium ion and hence these proteins are incapable of hydrolyzing phospholipids. In this work, the crystal structure of a Lys49-PLA(2) homologue from Bothrops brazili (MTX-II) was solved in two conformational states: (a) native, with Lys49 singly coordinated by the backbone oxygen atom of Val31 and (b) complexed with tetraethylene glycol (TTEG). Interestingly, the TTEG molecule was observed in two different coordination cages depending on the orientation of the nominal calcium-binding loop and of the residue Lys49. These structural observations indicate a direct role for the residue Lys49 in the functioning of a catalytically inactive PLA(2) homologue suggesting a contribution of the active site-like region in the expression of pharmacological effects such as myotoxicity and edema formation. Despite the several crystal structures of Lys49-PLA(2) homologues already determined, their biological assembly remains controversial with two possible conformations. The extended dimer with the hydrophobic channel exposed to the solvent and the compact dimer in which the active site-like region is occluded by the dimeric interface. In the MTX-II crystal packing analysis was found only the extended dimer as a possible stable quaternary arrangement.
 
Crystallographic portrayal of different conformational states of a Lys49 phospholipase A(2) homologue: Insights into structural determinants for myotoxicity and dimeric configuration.,Ullah A, Souza TA, Betzel C, Murakami MT, Arni RK Int J Biol Macromol. 2012 May 11. PMID:22584077<ref>PMID:22584077</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4dcf" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>

Revision as of 17:31, 14 March 2024

Structure of MTX-II from Bothrops braziliStructure of MTX-II from Bothrops brazili

Structural highlights

4dcf is a 4 chain structure with sequence from Bothrops brazili. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.7Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PA2H1_BOTBZ Snake venom phospholipase A2 homolog that lacks enzymatic activity. Is myotoxic and displays edema-inducing activities in mouse paw (PubMed:18602430). Also displays cytotoxic activity against some cell lines, and antimicrobial activities against E.coli, C.albicans and Leishmania (PubMed:18602430). 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:24145104). 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:24145104). The MDoS region stabilizes the toxin on membrane by the interaction of charged residues with phospholipid head groups (PubMed:24145104). Subsequently, the MDiS region destabilizes the membrane with penetration of hydrophobic residues (PubMed:24145104). 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:24145104).[1] [2]

References

  1. ↑ Costa TR, Menaldo DL, Oliveira CZ, Santos-Filho NA, Teixeira SS, Nomizo A, Fuly AL, Monteiro MC, de Souza BM, Palma MS, Stabeli RG, Sampaio SV, Soares AM. Myotoxic phospholipases A(2) isolated from Bothrops brazili snake venom and synthetic peptides derived from their C-terminal region: cytotoxic effect on microorganism and tumor cells. Peptides. 2008 Oct;29(10):1645-56. doi: 10.1016/j.peptides.2008.05.021. Epub 2008, Jun 5. PMID:18602430 doi:http://dx.doi.org/10.1016/j.peptides.2008.05.021
  2. ↑ Fernandes CA, Comparetti EJ, Borges RJ, Huancahuire-Vega S, Ponce-Soto LA, Marangoni S, Soares AM, Fontes MR. Structural bases for a complete myotoxic mechanism: Crystal structures of two non-catalytic phospholipases A-like from Bothrops brazili venom. Biochim Biophys Acta. 2013 Oct 18;1834(12):2772-2781. doi:, 10.1016/j.bbapap.2013.10.009. PMID:24145104 doi:http://dx.doi.org/10.1016/j.bbapap.2013.10.009

4dcf, resolution 2.70Å

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