3cxi

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Structure of BthTX-I complexed with alpha-tocopherol

Structural highlights

3cxi 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 1.83Å
Ligands:PE4, SO4, VIT
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 (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][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

Phospholipases A(2) (PLA(2)s) are membrane-associated enzymes that hydrolyze phospholipids at the sn-2 position, releasing lysophospholipids and free fatty acids. Phospholipase A(2) homologues (Lys49-PLA(2)s) are highly myotoxic and cause extensive tissue damage despite not showing measurable catalytic activity. They are found in different snake venoms and represent one third of bothropic venom composition. The importance of these toxins during envenomation is related to the pronounced local myotoxic effect they induce since this effect is not neutralized by serum therapy. We present herein three structures of Lys49-PLA(2)s from Bothrops genus snake venom crystallized under the same conditions, two of which were grown in the presence of alpha-tocopherol (vitamin E). Comparative structural analysis of these and other Lys49-PLA(2)s showed two different patterns of oligomeric conformation that are related to the presence or absence of ligands in the hydrophobic channel. This work also confirms the biological dimer indicated by recent studies in which both C-termini are in the dimeric interface. In this configuration, we propose that the myotoxic site of these toxins is composed by the Lys 20, Lys115 and Arg118 residues. For the first time, a residue from the short-helix (Lys20) is suggested as a member of this site and the importance of Tyr119 residue to myotoxicity of bothropic Lys49-PLA(2)s is also discussed. These results support a complete hypothesis for these PLA(2)s myotoxic activity consistent with all findings on bothropic Lys49-PLA(2)s studied up to this moment, including crystallographic, bioinformatics, biochemical and biophysical data.

Comparative structural studies on Lys49-phospholipases A(2) from Bothrops genus reveal their myotoxic site.,dos Santos JI, Soares AM, Fontes MR J Struct Biol. 2009 Aug;167(2):106-16. Epub 2009 May 3. PMID:19401234[10]

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

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Citations
3 reviews cite this structure
Snake venom Lys49 myotoxins: From phospholipases A(2) to non-enzymatic membrane disruptors.
Lomonte et al. (2012)
2 more
21 other articles
No citations found

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ dos Santos JI, Soares AM, Fontes MR. Comparative structural studies on Lys49-phospholipases A(2) from Bothrops genus reveal their myotoxic site. J Struct Biol. 2009 Aug;167(2):106-16. Epub 2009 May 3. PMID:19401234 doi:10.1016/j.jsb.2009.04.003

Contents


PDB ID 3cxi

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