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The interaction between the natural metalloendopeptidase inhibitor BJ46a and its target toxin jararhagin analyzed by structural mass spectrometry and molecular modeling.
Bastos, Viviane A; Gomes-Neto, Francisco; Rocha, Surza Lucia G; Teixeira-Ferreira, André; Perales, Jonas; Neves-Ferreira, Ana Gisele C; Valente, Richard H.
Afiliação
  • Bastos VA; Laboratory of Toxinology, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil.
  • Gomes-Neto F; Laboratory of Toxinology, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil.
  • Rocha SLG; Laboratory of Toxinology, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil.
  • Teixeira-Ferreira A; Laboratory of Toxinology, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil.
  • Perales J; Laboratory of Toxinology, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil.
  • Neves-Ferreira AGC; Laboratory of Toxinology, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil.
  • Valente RH; Laboratory of Toxinology, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil. Electronic address: richardhemmi@gmail.com.
J Proteomics ; 221: 103761, 2020 06 15.
Article em En | MEDLINE | ID: mdl-32247172
ABSTRACT
Snakebite envenoming affects millions of people worldwide, being officially considered a neglected tropical disease by the World Health Organization. The antivenom is effective in neutralizing the systemic effects of envenomation, but local effects are poorly neutralized, often leading to permanent disability. The natural resistance of the South American pit viper Bothrops jararaca to its venom is partly attributed to BJ46a, a natural snake venom metalloendopeptidase inhibitor. Upon complex formation, BJ46a binds non-covalently to the metalloendopeptidase, rendering it unable to exert its proteolytic activity. However, the structural features that govern this interaction are largely unknown. In this work, we applied structural mass spectrometry techniques (cross-linking-MS and hydrogen-deuterium exchange MS) and in silico analyses (molecular modeling, docking, and dynamics simulations) to understand the interaction between BJ46a and jararhagin, a metalloendopeptidase from B. jararaca venom. We explored the distance restraints generated from XL-MS experiments to guide the modeling of BJ46a and jararhagin, as well as the protein-protein docking simulations. HDX-MS data pinpointed regions of protection/deprotection at the interface of the BJ46a-jararhagin complex which, in addition to the molecular dynamics simulation data, reinforced our proposed interaction model. Ultimately, the structural understanding of snake venom metalloendopeptidases inhibition by BJ46a could lead to the rational design of drugs to improve anti-snake venom therapeutics, alleviating the high morbidity rates currently observed.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Bothrops / Venenos de Crotalídeos Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Bothrops / Venenos de Crotalídeos Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article