title: Water-molecule network and active-site flexibility of apo protein tyrosine phosphatase 1B.
abstract: Protein tyrosine phosphatase 1B (PTP1B) plays a key role as a negative regulator of insulin and leptin signalling and is therefore considered to be an important molecular target for the treatment of type 2 diabetes and obesity. Detailed structural information about the structure of PTP1B, including the conformation and flexibility of active-site residues as well as the water-molecule network, is a key issue in understanding ligand binding and enzyme kinetics and in structure-based drug design. A 1.95 A apo PTP1B structure has been obtained, showing four highly coordinated water molecules in the active-site pocket of the enzyme; hence, the active site is highly solvated in the apo state. Three of the water molecules are located at positions that approximately correspond to the positions of the phosphate O atoms of the natural substrate phosphotyrosine and form a similar network of hydrogen bonds. The active-site WPD-loop was found to be in the closed conformation, in contrast to previous observations of wild-type PTPs in the apo state, in which the WPD-loop is open. The closed conformation is stabilized by a network of hydrogen bonds. These results provide new insights into and understanding of the active site of PTP1B and form a novel basis for structure-based inhibitor design.
authors.affiliation: Protein Science, Novo Nordisk, DK-2880 Bagsvaerd, Denmark.
authors.forename: Anja K
authors.initials: AK
authors.lastname: Pedersen
authors.forename: G üNther H
authors.initials: Gü
authors.lastname: Peters G
authors.forename: Karin B
authors.initials: KB
authors.lastname: Møller
authors.forename: Lars F
authors.initials: LF
authors.lastname: Iversen
authors.forename: Jette S
authors.initials: JS
authors.lastname: Kastrup
mesh_terms: D001665:Binding Sites; D002384:Catalysis; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry; D008958:Models, Molecular; D011487:Protein Conformation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry*; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D007527:Isoenzymes; D014867:Water; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases