PONTES, Frederico José de Santana.; MAIA, Rafael Trindade.; LIMA, Maria Carolina P.; AYRES, Constância Flávia Junqueira.; SOARES, Thereza Amélia.
Abstract:
Glutathione S-transferases (GSTs) are enzymes capable of metabolizing cytotoxic compounds.
The enzyme AgGSTE2, member of epsilon class GSTs (GSTE), is the most important GST
conferring resistance to dichloro-diphenyl-trichloroethane (DDT) in Anopheles gambiae. We have
investigated the conformational dynamics of three GSTE variants (GSTE2, GSTE2-I114T/F120L,
GSTE5) from A. gambiae. Large-scale motions of helices H2 and H4 and conformational transition
of the C-terminal governs the opening of the G-site and is expected to affect substrate binding
and product release. This structural rearrangement places Glu116 (Glu120 in GSTE5) close of the
thiol group of the tripeptide glutathione (GSH) cofactor, making this residue a candidate to act as
a base in the activation of DDT. The structural rearrangement is noticeable for AgGSTE2-F120L,
which has been shown to confer increased DDT-resistance. The other variants exhibit a more subtle
rearrangement. These findings corroborate the hypothesis that the increase of the conformational
dynamics of GST Epsilon class isoforms from A. gambiae promotes higher DDTase activity.