Water-molecule network and active-site flexibility of apo protein tyrosine phosphatase 1B
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Water-molecule network and active-site flexibility of apo protein tyrosine phosphatase 1B. / Pedersen, Anja Kallesøe; Peters G, G üNther H; Møller, Karin B; Iversen, Lars F; Kastrup, Jette Sandholm Jensen.
In: Acta Crystallographica. Section D: Biological Crystallography, Vol. 60, No. Pt 9, 09.2004, p. 1527-34.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Water-molecule network and active-site flexibility of apo protein tyrosine phosphatase 1B
AU - Pedersen, Anja Kallesøe
AU - Peters G, G üNther H
AU - Møller, Karin B
AU - Iversen, Lars F
AU - Kastrup, Jette Sandholm Jensen
PY - 2004/9
Y1 - 2004/9
N2 - 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.
AB - 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.
KW - Binding Sites
KW - Catalysis
KW - Humans
KW - Isoenzymes
KW - Models, Molecular
KW - Protein Conformation
KW - Protein Tyrosine Phosphatase, Non-Receptor Type 1
KW - Protein Tyrosine Phosphatases
KW - Water
KW - X-Ray Diffraction
U2 - 10.1107/S0907444904015094
DO - 10.1107/S0907444904015094
M3 - Journal article
C2 - 15333922
VL - 60
SP - 1527
EP - 1534
JO - Acta Crystallographica Section D: Structural Biology
JF - Acta Crystallographica Section D: Structural Biology
SN - 2059-7983
IS - Pt 9
ER -
ID: 44729794