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Structural and functional studies with mytoxin II from Bothrops moojeni reveal remarkable similarities and differences compared to other catalytically inactive phospholipases A₂-like.

Salvador GH, Cavalcante WL, Dos Santos JI, Gallacci M, Soares AM, Fontes MR
Toxicon 72 52-63 (2013)
Cited: 14 times
EuropePMC logo PMID: 23810946

Abstract

Lys49-phospholipases A₂ (Lys49-PLA₂s) are proteins found in bothropic snake venoms (Viperidae family) and belong to a class of proteins which presents a phospholipase A2 scaffold but are catalytically inactive. These proteins (also known as PLA₂s-like toxins) exert a pronounced local myotoxic effect and are not neutralized by antivenom, being their study relevant in terms of medical and scientific interest. Despite of the several studies reported in the literature for this class of proteins only a partial consensus has been achieved concerning their functional-structural relationships. In this work, we present a comprehensive structural and functional study with the MjTX-II, a dimeric Lys49-PLA₂ from Bothrops moojeni venom which includes: (i) high-resolution crystal structure; (ii) dynamic light scattering and bioinformatics studies in order to confirm its biological assembly; (iii) myographic and electrophysiological studies and, (iv) comparative studies with other Lys49-PLA₂s. These comparative analyses let us to get important insights into the role of Lys122 amino acid, previously indicated as responsible for Lys49-PLA₂s catalytic inactivity and added important elements to establish the correct biological assembly for this class of proteins. Furthermore, we show two unique sequential features of MjTX-II (an amino acid insertion and a mutation) in comparison to all bothropic Lys49-PLA₂s that lead to a distinct way of ligand binding at the toxin's hydrophobic channel and also, allowed the presence of an additional ligand molecule in this region. These facts suggest a possible particular mode of binding for long-chain ligands that interacts with MjTX-II hydrophobic channel, a feature that may directly affect the design of structure-based ligands for Lys49-PLA₂s.

Articles - 4kf3 mentioned but not cited (4)

  1. Structural basis for phospholipase A2-like toxin inhibition by the synthetic compound Varespladib (LY315920). Salvador GHM, Gomes AAS, Bryan-Quirós W, Fernández J, Lewin MR, Gutiérrez JM, Lomonte B, Fontes MRM. Sci Rep 9 17203 (2019)
  2. Structural and functional characterization of suramin-bound MjTX-I from Bothrops moojeni suggests a particular myotoxic mechanism. Salvador GHM, Dreyer TR, Gomes AAS, Cavalcante WLG, Dos Santos JI, Gandin CA, de Oliveira Neto M, Gallacci M, Fontes MRM. Sci Rep 8 10317 (2018)
  3. PLA2-like proteins myotoxic mechanism: a dynamic model description. Borges RJ, Lemke N, Fontes MRM. Sci Rep 7 15514 (2017)
  4. Search for efficient inhibitors of myotoxic activity induced by ophidian phospholipase A2-like proteins using functional, structural and bioinformatics approaches. Salvador GHM, Cardoso FF, Gomes AA, Cavalcante WLG, Gallacci M, Fontes MRM. Sci Rep 9 510 (2019)


Articles citing this publication (10)

  1. Structural bases for a complete myotoxic mechanism: crystal structures of two non-catalytic phospholipases A2-like from Bothrops brazili venom. Fernandes CA, Comparetti EJ, Borges RJ, Huancahuire-Vega S, Ponce-Soto LA, Marangoni S, Soares AM, Fontes MR. Biochim Biophys Acta 1834 2772-2781 (2013)
  2. Structural Basis for the Inhibition of a Phospholipase A2-Like Toxin by Caffeic and Aristolochic Acids. Fernandes CA, Cardoso FF, Cavalcante WG, Soares AM, Dal-Pai M, Gallacci M, Fontes MR. PLoS One 10 e0133370 (2015)
  3. CoaTx-II, a new dimeric Lys49 phospholipase A2 from Crotalus oreganus abyssus snake venom with bactericidal potential: Insights into its structure and biological roles. Almeida JR, Lancellotti M, Soares AM, Calderon LA, Ramírez D, González W, Marangoni S, Da Silva SL. Toxicon 120 147-158 (2016)
  4. Structural and functional evidence for membrane docking and disruption sites on phospholipase A2-like proteins revealed by complexation with the inhibitor suramin. Salvador GH, Dreyer TR, Cavalcante WL, Matioli FF, Dos Santos JI, Velazquez-Campoy A, Gallacci M, Fontes MR. Acta Crystallogr D Biol Crystallogr 71 2066-2078 (2015)
  5. Photobiostimulation reduces edema formation induced in mice by Lys-49 phospholipases A2 isolated from Bothrops moojeni venom. Nadur-Andrade N, Dale CS, Santos AS, Soares AM, de Lima CJ, Zamuner SR. Photochem Photobiol Sci 13 1561-1567 (2014)
  6. SDS-induced oligomerization of Lys49-phospholipase A2 from snake venom. Matsui T, Kamata S, Ishii K, Maruno T, Ghanem N, Uchiyama S, Kato K, Suzuki A, Oda-Ueda N, Ogawa T, Tanaka Y. Sci Rep 9 2330 (2019)
  7. EC-PIII, a novel non-hemorrhagic procoagulant metalloproteinase: Purification and characterization from Indian Echis carinatus venom. Choudhury M, Suvilesh KN, Vishwanath BS, Velmurugan D. Int J Biol Macromol 106 193-199 (2018)
  8. Isolation and Characterization of A2-EPTX-Nsm1a, a Secretory Phospholipase A2 from Malaysian Spitting Cobra (Naja sumatrana) Venom. Abdullah NAH, Rusmili MRA, Zainal Abidin SA, Shaikh MF, Hodgson WC, Othman I. Toxins (Basel) 13 859 (2021)
  9. The allosteric activation mechanism of a phospholipase A2-like toxin from Bothrops jararacussu venom: a dynamic description. Gomes AAS, Cardoso FF, Souza MF, Oliveira CLP, Perahia D, Magro AJ, Fontes MRM. Sci Rep 10 16252 (2020)
  10. DOCLASP - Docking ligands to target proteins using spatial and electrostatic congruence extracted from a known holoenzyme and applying simple geometrical transformations. Chakraborty S. F1000Res 3 262 (2014)


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