A targeted molecular dynamics study of WPD loop movement in PTP1B.
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.
Kamerlin
Shina Caroline Lynn
SC
Institute for Biomolecular Structural Chemistry, University of Vienna, Währingerstrasse 17, A-1090, Vienna, Austria. L.Kamerlin@gmx.at
Rucker
Robert
R
Boresch
Stefan
S
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
C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases