PDBsum entry 1t4j

Hydrolase

PDB id: 1t4j

Contents

Protein chain

282 a.a. *

Ligands

FRJ

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Allosteric inhibition of protein tyrosine phosphatase 1b.

Authors

C.Wiesmann, K.J.Barr, J.Kung, J.Zhu, D.A.Erlanson, W.Shen, B.J.Fahr, M.Zhong, L.Taylor, M.Randal, R.S.Mcdowell, S.K.Hansen.

Ref.

Nat Struct Mol Biol, 2004, 11, 730-737. [DOI no: 10.1038/nsmb803]

PubMed id

15258570

Abstract

Obesity and type II diabetes are closely linked metabolic syndromes that afflict >100 million people worldwide. Although protein tyrosine phosphatase 1B (PTP1B) has emerged as a promising target for the treatment of both syndromes, the discovery of pharmaceutically acceptable inhibitors that bind at the active site remains a substantial challenge. Here we describe the discovery of an allosteric site in PTP1B. Crystal structures of PTP1B in complex with allosteric inhibitors reveal a novel site located approximately 20 A from the catalytic site. We show that allosteric inhibitors prevent formation of the active form of the enzyme by blocking mobility of the catalytic loop, thereby exploiting a general mechanism used by tyrosine phosphatases. Notably, these inhibitors exhibit selectivity for PTP1B and enhance insulin signaling in cells. Allosteric inhibition is a promising strategy for targeting PTP1B and constitutes a mechanism that may be applicable to other tyrosine phosphatases.

Figure 2.
Figure 2. Crystal structures reveal a novel allosteric site in PTP1B. (a) Inhibitor 2 (spheres) binds in a groove formed by helices 3 and 6 that positions the catalytically important WPD loop. Distance from the active site Cys is 20 Å. (b) Compound 2 binds in a hydrophobic pocket formed by Leu192, Phe196 and Phe280. Hydrogen bonds with side chains of Glu276, Asn193 and the main chain carbonyl of Phe196 (water-mediated) are shown. (c) Overlay of the crystal structures of compounds 1 (orange, 2.2-Å resolution), 2 (yellow, 1.9-Å resolution) and 3 (blue sticks and mesh, 2.7 Å resolution). The benzofuran core of the three compounds occupies the same hydrophobic site. Allosteric inhibitors progressively wrap around Phe280, correlating with increasing potency. PTP1B and the side chain of Phe280 are gray. This figure was created using PyMOL (DeLano Scientific; http://www.pymol.org).

Figure 7.
Figure 7. The allosteric-bound conformation is similar to conformations of PTP1B with the WPD loop in the open conformation. (a) Overlay of 16 structures of PTP1B with the WPD loop in the open conformation (black), along with PTP1B bound to compound 2 (spheres, protein in magenta), and the closed conformation (green, PDB entry 1PTY). Alignment shows that the allosteric-bound conformation is similar to many open conformations. (b) Allosteric inhibitor binds to the naturally occurring open conformation (E[o]) of PTP1B and inhibits activity by blocking closure of the WPD loop. Compound cannot bind to the closed conformation.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Mol Biol (2004, 11, 730-737) copyright 2004.