title: Characterization of suramin binding sites on the human group IIA secreted phospholipase A2 by site-directed mutagenesis and molecular dynamics simulation.
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.
authors.affiliation: Department of Chemistry, FFCLRP-USP, Universidade de São Paulo, Brazil.
authors.forename: Elisângela Aparecida
authors.initials: EA
authors.lastname: Aragão
authors.forename: Davi Serradella
authors.initials: DS
authors.lastname: Vieira
authors.forename: Lucimara
authors.initials: L
authors.lastname: Chioato
authors.forename: Tatiana Lopes
authors.initials: TL
authors.lastname: Ferreira
authors.forename: Marcos Roberto
authors.initials: MR
authors.lastname: Lourenzoni
authors.forename: Samuel Reghim
authors.initials: SR
authors.lastname: Silva
authors.forename: Richard John
authors.initials: RJ
authors.lastname: Ward
mesh_terms: D001665:Binding Sites; D005452:Fluoresceins / Q000737:chemistry; D054501:Group II Phospholipases A2 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008081:Liposomes / Q000737:chemistry; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D013050:Spectrometry, Fluorescence; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013498:Suramin / Q000737:chemistry*
chemical_list: D005452:Fluoresceins; D008081:Liposomes; D011994:Recombinant Proteins; D013498:Suramin; D054501:Group II Phospholipases A2; C007740:fluorexon