title: Molecular recognition of 15-deoxy-delta(12,14)-prostaglandin J2 by nuclear factor-kappa B and other cellular proteins.
abstract: 15-Deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2), a dehydration product of prostaglandin D2, is an important pharmacological molecule, which with the virtue of its electrophilicity, has been reported to covalently modify some cellular proteins (such as nuclear factor-kappa B (NF-kappaB), AP-1, p53, and thioredoxin) and elicit its physiological effects. The aim of the present computational study is to understand the role molecular recognition plays in the association of 15d-PGJ2 with NF-kappaB and other proteins. Another aim is to characterize whether p53 is a direct target for covalent modification by 15d-PGJ2. A docking strategy is applied along with calculation of ab initio electrostatic potential maps to analyze the mode of binding of prostaglandin molecule with critical cysteine-containing sites in each protein. The results provide identification of important sites in the target proteins, which provide recognition and stability to the prostaglandin molecule. Fit of shape and complementarity of electrostatic interactions are derived as significant determinants of molecular recognition of 15d-PGJ2. Further, comparative results indicate that p53 protein may also be a target for direct modification by 15d-PGJ2. The molecular models obtained should allow the rational design of more specific analogs of 15d-PGJ2.
authors: REQUIMTE/Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal.
authors: Vineet
authors: V
authors: Pande
authors: Maria J
authors: MJ
authors: Ramos
mesh_terms: D001665:Binding Sites; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D048031:JNK Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D016328:NF-kappa B / Q000737:chemistry* / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D055672:Static Electricity; D013379:Substrate Specificity; D013879:Thioredoxins / Q000737:chemistry / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism
chemical_list: C477819:15-deoxyprostaglandin J2; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D013879:Thioredoxins; D048031:JNK Mitogen-Activated Protein Kinases; D015230:Prostaglandin D2