title: Human retinoblastoma binding protein 9, a serine hydrolase implicated in pancreatic cancers.
abstract: 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-β signalling pathway. Sequence analysis suggests that RBBP9 belongs to the α/β hydrolase superfamily of enzymes. The serine hydrolase activity of RBBP9 is required for development of pancreatic carcinomas in part by inhibiting TGF-β antiproliferative signaling through suppressing Smad2/3 phosphorylation. The crystal structure of human RBBP9 confirms the α/β hydrolase fold, with a six-stranded parallel β-sheet flanked by α 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.
authors.affiliation: Department of Biological Sciences, Northeast Structural Genomics Consortium, Columbia University, New York, NY 10027, USA.
authors.forename: Sergey M
authors.initials: SM
authors.lastname: Vorobiev
authors.forename: Yuanpeng Janet
authors.initials: YJ
authors.lastname: Huang
authors.forename: Jayaraman
authors.initials: J
authors.lastname: Seetharaman
authors.forename: Rong
authors.initials: R
authors.lastname: Xiao
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Acton
authors.forename: Gaetano T
authors.initials: GT
authors.lastname: Montelione
authors.forename: Liang
authors.initials: L
authors.lastname: Tong
mesh_terms: D002277:Carcinoma / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D011487:Protein Conformation; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; C485185:RBBP9 protein, human; D012697:Serine Endopeptidases