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Ya. A. Sharapova, V. K. Švedas
Molecular
modeling of an allosteric inhibitor optactin’s binding in the new binding site
in neuraminidase a from streptococcus pneumoniae
Abstract
Neuraminidase A
(NanA) from the pathogenic bacteria Streptococcus pneumoniae catalyzes the
cleavage of terminal sialic acid residues from oligosaccharide receptors on the
surface of human respiratory epithelium cells and is considered as the key
virulence factor. Search for new regulatory ligands’ binding sites in the
structure of this enzyme is of fundamental interest and can reveal new targets
to design drugs for treatment of pneumonia, meningitis and other human
infectious diseases. A low molecular weight compound optactin has been recently
shown to inhibit the activity of the homologous Neuraminidase B (NanB).
Furthermore, optactin binds at a separate site in the protein’s structure,
which is topologically different from the catalytic center. Bioinformatic and
structure analysis using the pocketZebra method has been carried out to
annotate the new, previously unknown site in the NanA’s structure. This new
site is analogous to the optactin binding site in NanB, and is characterized by
a high content of the subfamily-specific positions, that indicate the
importance of this site for the enzyme function. Molecular modeling has been
used to study how the optactin binds in the allosteric sites of homologous
neuraminidases NanA and NanB. Tyr250, Thr251, Lys334, Gln494, Lys499, Lys597,
Thr657, Glu658 residues were shown to stabilize the optactin molecule in the
NanB’ structure, with water molecules playing an important role in the ligand
coordination. Molecular modeling has shown that the optactin binding by the NanA
is complicated due to substitutions in the subfamily-specific positions of the
allosteric center. Pecularities in the structural organization of the new
NanA’s binding site can help to design complementary ligands that can
selectively regulate the activity of this enzyme.
Key words:
allosteric site, bacterial neuraminidases from Streptococcus pneumoniae,
NanA, NanB, optactin inhibitor, bioinformatic analysis, molecular modeling.
Copyright (C) Chemistry Dept., Moscow State University, 2002
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