Signal transfer in human protein tyrosine phosphatase PTP1B from allosteric inhibitor P00058

Abstract

Protein tyrosine phosphatases constitute a family of cytosolic and receptor-like signal transducing enzymes that catalyze the hydrolysis of phospho-tyrosine residues of phosphorylated proteins. PTP1B, encoded by PTPN1, is a key negative regulator of insulin and leptin receptor signaling, linking it to two widespread diseases: type 2 diabetes mellitus and obesity. Here, we present crystal structures of the PTP1B apo-enzyme and a complex with a newly identified allosteric inhibitor, 2-(2,5-dimethyl-pyrrol-1-yl)-5-hydroxy-benzoic acid, designated as P00058. The inhibitor binding site is located about 18 Å away from the active center. However, the inhibitor causes significant re-arrangements in the active center of enzyme: residues 45–50 of catalytic Tyr-loop are shifted at their Cα-atom positions by 2.6 to 5.8 Å. We have identified an event of allosteric signal transfer from the inhibitor to the catalytic area using molecular dynamic simulation. Analyzing change of complex structure along the fluctuation trajectory we have found the large Cα-atom shifts in external strand, residues 25–40, which occur at the same time with the shifts in adjacent catalytic p-Tyr-loop. Coming of the signal to this loop arises due to dynamic fluctuation of protein structure at about 4.0 nanoseconds after the inhibitor takes up its space.

Communicated by Ramaswamy H. Sarma

Keywords:

• Protein tyrosine phosphatase
• PTP1B
• allosteric inhibitor
• signal transfer

Acknowledgements

The authors thank Prof Alexander V. Efimov, Institute of Protein Research, Russian Academy of Sciences, for interest to this work and his ongoing support. This research used resources of the Advanced Photon Source, a U.S. Department of Energy Office of Science User Facility operated for the Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Use of the Lilly Research Laboratories Collaborative Access Team beamline at Sector 31 of the Advanced Photon Source was provided by Eli Lilly and Company, which operates the facility. The authors acknowledge a grant from the Ontario Research and Development Challenge Fund (99-SEP-0512). EFP was supported by the Canada Research Program.

Disclosure statement

No potential conflict of interest was reported by the authors.

Funding

The author(s) reported there is no funding associated with the work featured in this article.