Structural basis for inhibition of protein-tyrosine phosphatase 1B by isothiazolidinone heterocyclic phosphonate mimetics.
Crystal structures of protein-tyrosine phosphatase 1B in complex with compounds bearing a novel isothiazolidinone (IZD) heterocyclic phosphonate mimetic reveal that the heterocycle is highly complementary to the catalytic pocket of the protein. The heterocycle participates in an extensive network of hydrogen bonds with the backbone of the phosphate-binding loop, Phe(182) of the flap, and the side chain of Arg(221). When substituted with a phenol, the small inhibitor induces the closed conformation of the protein and displaces all waters in the catalytic pocket. Saturated IZD-containing peptides are more potent inhibitors than unsaturated analogs because the IZD heterocycle and phenyl ring directly attached to it bind in a nearly orthogonal orientation with respect to each other, a conformation that is close to the energy minimum of the saturated IZD-phenyl moiety. These results explain why the heterocycle is a potent phosphonate mimetic and an ideal starting point for designing small nonpeptidic inhibitors.
Ala
Paul J
PJ
Incyte Corporation, Experimental Station, Route 141 and Henry Clay Road, Wilmington, DE 19880, USA. pauljala@gmail.com
Gonneville
Lucie
L
Hillman
Milton C
MC
Becker-Pasha
Mary
M
Wei
Min
M
Reid
Brian G
BG
Klabe
Ronald
R
Yue
Eddy W
EW
Wayland
Brian
B
Douty
Brent
B
Polam
Padmaja
P
Wasserman
Zelda
Z
Bower
Michael
M
Combs
Andrew P
AP
Burn
Timothy C
TC
Hollis
Gregory F
GF
Wynn
Richard
R
D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D063065:Organophosphonates / Q000494:pharmacology*; D011487:Protein Conformation / Q000187:drug effects; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000302:isolation & purification; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013844:Thiazoles / Q000494:pharmacology*; D014867:Water / Q000737:chemistry
D063065:Organophosphonates; D013844:Thiazoles; C512915:isothiazolidinone; D014867:Water; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases