Flexibility and inhibitor binding in Cdc25 phosphatases

Autor(es)

Arantes, Guilherme Menegon ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Quim, BR-05508900 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS; v. 78, n. 14, p. 3017-3032, NOV 1 2010.
• Citações Web of Science: 10

Resumo

Cdc25 phosphatases involved in cell cycle checkpoints are now active targets for the development of anti-cancer therapies. Rational drug design would certainly benefit from detailed structural information for Cdc25s. However, only apo- or sulfate-bound crystal structures of the Cdc25 catalytic domain have been described so far. Together with previously available crystalographic data, results from molecular dynamics simulations, bioinformatic analysis, and computer-generated conformational ensembles shown here indicate that the last 30-40 residues in the C-terminus of Cdc25B are partially unfolded or disordered in solution. The effect of C-terminal flexibility upon binding of two potent small molecule inhibitors to Cdc25B is then analyzed by using three structural models with variable levels of flexibility, including an equilibrium distributed ensemble of Cdc25B backbone conformations. The three Cdc25B structural models are used in combination with flexible docking, clustering, and calculation of binding free energies by the linear interaction energy approximation to construct and validate Cdc25B-inhibitor complexes. Two binding sites are identified on top and beside the Cdc25B active site. The diversity of interaction modes found increases with receptor flexibility. Backbone flexibility allows the formation of transient cavities or compact hydrophobic units on the surface of the stable, folded protein core that are unexposed or unavailable for ligand binding in rigid and densely packed crystal structures. The present results may help to speculate on the mechanisms of small molecule complexation to partially unfolded or locally disordered proteins. (AU)

• Processo FAPESP: 07/59345-6 - Simulacao computacional em bioquimica: estrutura eletronica de agregados polinucleares em metaloenzimas e ligacao de inibidores a proteinas tirosina-fosfatases.
• Beneficiário: Guilherme Menegon Arantes
• Modalidade de apoio: Bolsas no Brasil - Jovens Pesquisadores
• Processo FAPESP: 07/52772-6 - Simulação computacional em bioquímica: estrutura eletrônica de agregados polinucleares em metaloenzimas e ligação de inibidores a proteínas tirosina-fosfatases
• Beneficiário: Guilherme Menegon Arantes
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores