Vorobiev, S.M., Su, M., Seetharaman, J., Kuzin, A., Chen, C.X., Cunningham, K., Owens, L., Xiao, R., Acton, T.B., Montelione, G.T., Hunt, J.F., Tong, L.
Human retinoblastoma binding protein 9 (RBBP9) is an interacting partner of the retinoblastoma susceptibility protein (Rb). RBBP9 is a tumor-associated protein required for pancreatic neoplasia, affects cell cycle control, and is involved in the TGF-beta signalling pathway. Sequence analysis suggests that RBBP9 belongs to the alpha/beta hydrolase superfamily of enzymes. The serine hydrolase activity of RBBP9 is required for development of pancreatic carcinomas in part by inhibiting TGF-beta antiproliferative signaling through suppressing Smad2/3 phosphorylation. The crystal structure of human RBBP9 confirms the alpha/beta hydrolase fold, with a six-stranded parallel beta-sheet flanked by alpha helixes. The structure of RBBP9 resembles that of the YdeN protein from Bacillus subtilis, which is suggested to have carboxylesterase activity. RBBP9 contains a Ser75-His165-Asp138 catalytic triad, situated in a prominent pocket on the surface of the protein. The side chains of the LxCxE sequence motif that is important for interaction with Rb is mostly buried in the structure. Structure- function studies of RBBP9 suggest possible routes for novel cancer drug discovery programs.
