title: Engineering the catalytic domain of human protein tyrosine phosphatase beta for structure-based drug discovery.
abstract: Protein tyrosine phosphatases (PTPs) play roles in many biological processes and are considered to be important targets for drug discovery. As inhibitor development has proven challenging, crystal structure-based design will be very helpful to advance inhibitor potency and selectivity. Successful application of protein crystallography to drug discovery heavily relies on high-quality crystal structures of the protein of interest complexed with pharmaceutically interesting ligands. It is very important to be able to produce protein-ligand crystals rapidly and reproducibly for as many ligands as necessary. This study details our efforts to engineer the catalytic domain of human protein tyrosine phosphatase beta (HPTPbeta-CD) with properties suitable for rapid-turnaround crystallography. Structures of apo HPTPbeta-CD and its complexes with several novel small-molecule inhibitors are presented here for the first time.
authors.affiliation: Structural Biology, Procter and Gamble Pharmaceuticals, 8700 Mason-Montgomery Road, Mason, OH 45140, USA. artem@xtals.org
authors.forename: Artem G
authors.initials: AG
authors.lastname: Evdokimov
authors.forename: Matthew
authors.initials: M
authors.lastname: Pokross
authors.forename: Richard
authors.initials: R
authors.lastname: Walter
authors.forename: Marlene
authors.initials: M
authors.lastname: Mekel
authors.forename: Brooke
authors.initials: B
authors.lastname: Cox
authors.forename: Chuiying
authors.initials: C
authors.lastname: Li
authors.forename: Randy
authors.initials: R
authors.lastname: Bechard
authors.forename: Frank
authors.initials: F
authors.lastname: Genbauffe
authors.forename: Ryan
authors.initials: R
authors.lastname: Andrews
authors.forename: Conrad
authors.initials: C
authors.lastname: Diven
authors.forename: Brian
authors.initials: B
authors.lastname: Howard
authors.forename: Vinit
authors.initials: V
authors.lastname: Rastogi
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Gray
authors.forename: Matthew
authors.initials: M
authors.lastname: Maier
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Peters
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015202:Protein Engineering; D017433:Protein Structure, Secondary; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D017027:Protein Tyrosine Phosphatases