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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Characterization of suramin binding sites on the human group IIA secreted phospholipase A(2) by site-directed mutagenesis and molecular dynamics simulation

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Author(s):
Aragao, Elisangela Aparecida ; Vieira, Davi Serradella ; Chioato, Lucimara [1] ; Ferreira, Tatiana Lopes [1] ; Lourenzoni, Marcos Roberto ; Silva, Samuel Reghim [2] ; Ward, Richard John [3]
Total Authors: 7
Affiliation:
[1] Univ Sao Paulo, FMRP USP, Dept Biochem & Immunol, BR-14040901 Ribeirao Preto, SP - Brazil
[2] Univ Fed Sao Carlos, Dept Comp Sci, BR-13560 Sao Carlos, SP - Brazil
[3] Univ Sao Paulo, Fac Filosofia Ciencias & Letras Ribeirao Preto, Dept Quim, FFCLRP USP, BR-14040901 Ribeirao Preto, SP - Brazil
Total Affiliations: 3
Document type: Journal article
Source: Archives of Biochemistry and Biophysics; v. 519, n. 1, p. 17-22, MAR 1 2012.
Web of Science Citations: 0
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 h5PLA2GIIA/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. (C) 2012 Elsevier Inc. All rights reserved. (AU)

FAPESP's process: 09/13902-7 - Characterization of synthetic and natural inhibitors of the human secreted phospholipase A2 of the group IIA
Grantee:Elisângela Aparecida Aragão
Support Opportunities: Scholarships in Brazil - Post-Doctoral