title: A targeted molecular dynamics study of WPD loop movement in PTP1B.
abstract: Targeted molecular dynamics was used to examine the mechanism of WPD loop closure in PTP1B, which is essential for the activity of the enzyme. Two important regions are identified: the R-loop (residues 113-118), which assists in substrate binding, and the S-loop (residues 198-209), which undergoes a conformational change that appears to be vital for the movement of the WPD loop. The S-loop is adjacent to the alpha3-helix, and its conformational change is coupled with a change of interactions between the alpha3- and alpha7-helices. This latter observation is of particular interest in connection with a novel class of allosteric inhibitors of PTP1B [Wiesmann et al., Nat. Struc. Mol. Biol. 11 (2004) 730-737]. These compounds prevent the closure of the WPD loop, forcing the enzyme to remain in a catalytically inactive conformation, by blocking the rearrangement of the alpha3-helix relative to the alpha7-helix.
authors.affiliation: Institute for Biomolecular Structural Chemistry, University of Vienna, Währingerstrasse 17, A-1090, Vienna, Austria. L.Kamerlin@gmx.at
authors.forename: Shina Caroline Lynn
authors.initials: SC
authors.lastname: Kamerlin
authors.forename: Robert
authors.initials: R
authors.lastname: Rucker
authors.forename: Stefan
authors.initials: S
authors.lastname: Boresch
mesh_terms: D000495:Allosteric Site; D001665:Binding Sites; D006801:Humans; D008968:Molecular Conformation; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry*; D055672:Static Electricity; D013997:Time Factors
chemical_list: C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases