Characterization of suramin binding sites on the human group IIA secreted phospholipase A2 by site-directed mutagenesis and molecular dynamics simulation.
Arch Biochem Biophys
; 519(1): 17-22, 2012 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-22248627
ABSTRACT
Suramin is a polysulphonated naphthylurea with inhibitory activity against the human secreted group IIA phospholipase A(2) (hsPLA2GIIA), and we have investigated suramin binding to recombinant hsPLA2GIIA using site-directed mutagenesis and molecular dynamics (MD) simulations. The changes in suramin binding affinity of 13 cationic residue mutants of the hsPLA2GIIA was strongly correlated with alterations in the inhibition of membrane damaging activity of the protein. Suramin binding to hsPLA2GIIA was also studied by MD simulations, which demonstrated that altered intermolecular potential energy of the suramin/mutant complexes was a reliable indicator of affinity change. Although residues in the C-terminal region play a major role in the stabilization of the hsPLA2GIIA/suramin complex, attractive and repulsive hydrophobic and electrostatic interactions with residues throughout the protein together with the adoption of a bent suramin conformation, all contribute to the stability of the complex. Analysis of the hsPLA2GIIA/suramin interactions allows the prediction of the properties of suramin analogues with improved binding and higher affinities which may be candidates for novel phospholipase A(2) inhibitors.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Suramina
/
Fosfolipases A2 do Grupo II
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Arch Biochem Biophys
Ano de publicação:
2012
Tipo de documento:
Article