Streptococcus pneumoniae TIGR4 flavodoxin: Structural and biophysical characterization of a novel drug target

Rodríguez Cárdenas, Ángela; Sancho Sanz, Javier; Hurtado Guerrero, Ramon; Conde Giménez, María; Rojas, A. L.; Velázquez Campoy, Adrián

doi:10.1371/journal.pone.0161020

Streptococcus pneumoniae TIGR4 flavodoxin: Structural and biophysical characterization of a novel drug target

Rodríguez Cárdenas, Ángela ; Rojas, A. L. ; Conde Giménez, María (Universidad de Zaragoza) ; Velázquez Campoy, Adrián (Universidad de Zaragoza) ; Hurtado Guerrero, Ramon (Universidad de Zaragoza) ; Sancho Sanz, Javier (Universidad de Zaragoza)

Resumen: Streptococcus pneumoniae (Sp) strain TIGR4 is a virulent, encapsulated serotype that causes bacteremia, otitis media, meningitis and pneumonia. Increased bacterial resistance and limited efficacy of the available vaccine to some serotypes complicate the treatment of diseases associated to this microorganism. Flavodoxins are bacterial proteins involved in several important metabolic pathways. The Sp flavodoxin (Spfld) gene was recently reported to be essential for the establishment of meningitis in a rat model, which makes SpFld a potential drug target. To facilitate future pharmacological studies, we have cloned and expressed SpFld in E. coli and we have performed an extensive structural and biochemical characterization of both the apo form and its active complex with the FMN cofactor. SpFld is a short-chain flavodoxin containing 146 residues. Unlike the well-characterized long-chain apoflavodoxins, the Sp apoprotein displays a simple two-state thermal unfolding equilibrium and binds FMN with moderate affinity. The X-ray structures of the apo and holo forms of SpFld differ at the FMN binding site, where substantial rearrangement of residues at the 91-100 loop occurs to permit cofactor binding. This work will set up the basis for future studies aiming at discovering new potential drugs to treat S. pneumoniae diseases through the inhibition of SpFld.
Idioma: Inglés
DOI: 10.1371/journal.pone.0161020
Año: 2016
Publicado en: PLoS One 11, 9 (2016), 0161020 [25pp]
ISSN: 1932-6203
Financiación: info:eu-repo/grantAgreement/ES/DGA/B89
Financiación: info:eu-repo/grantAgreement/EUR/FP7/BIOSTRUCTX-7687
Financiación: info:eu-repo/grantAgreement/ES/MICINN/BFU2010-16297
Financiación: info:eu-repo/grantAgreement/ES/MICINN/BFU2010-19504
Financiación: info:eu-repo/grantAgreement/ES/MICINN/CTQ2013-44367-C2-2-P
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2013-47064-P
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BIO2014-57314-REDT
Tipo y forma: Article (Published version)
Área (Departamento): Bioquímica y Biología Molecular (Departamento de Bioquímica y Biología Molecular y Celular)
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Notice créée le 2016-12-13, modifiée le 2016-12-13

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Streptococcus pneumoniae TIGR4 flavodoxin: Structural and biophysical characterization of a novel drug target