PDBsum entry 4ge6

Hydrolase/hydrolase inhibitor

PDB id: 4ge6

Contents

Protein chains

303 a.a.

Ligands

B26

Waters ×200

PDB id:

4ge6

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of human protein tyrosine phosphatase ptpn9 (meg2) complex with compound 7

Structure:

Tyrosine-protein phosphatase non-receptor type 9. Chain: a, b. Fragment: tyrosine-protein phosphatase domain (unp residues 277-582). Synonym: protein-tyrosine phosphatase meg2, ptpase meg2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ptpn9. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.40Å R-factor: 0.198 R-free: 0.215

Authors:

Z.-Y.Zhang,S.Liu,S.Zhang

Key ref:

S.Zhang et al. (2012). A highly selective and potent PTP-MEG2 inhibitor with therapeutic potential for type 2 diabetes. J Am Chem Soc, 134, 18116-18124. PubMed id: 23075115

Date:

01-Aug-12 Release date: 31-Oct-12

Protein chains

P43378  (PTN9_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 9 from Homo sapiens

Seq: 593 a.a.

Struc: 303 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.1.3.48 - protein-tyrosine-phosphatase.
• Reaction: O-phospho-L-tyrosyl-[protein] + H2O = L-tyrosyl-[protein] + phosphate

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Key reference

J Am Chem Soc 134:18116-18124 (2012)

PubMed id: 23075115

A highly selective and potent PTP-MEG2 inhibitor with therapeutic potential for type 2 diabetes.

S.Zhang, S.Liu, R.Tao, D.Wei, L.Chen, W.Shen, Z.H.Yu, L.Wang, D.R.Jones, X.C.Dong, Z.Y.Zhang.

ABSTRACT

Protein tyrosine phosphatases (PTPs) constitute a large family of signaling enzymes that control the cellular levels of protein tyrosine phosphorylation. A detailed understanding of PTP functions in normal physiology and in pathogenic conditions has been hampered by the absence of PTP-specific, cell-permeable small-molecule agents. We present a stepwise focused library approach that transforms a weak and general non-hydrolyzable pTyr mimetic (F(2)Pmp, phosphonodifluoromethyl phenylalanine) into a highly potent and selective inhibitor of PTP-MEG2, an antagonist of hepatic insulin signaling. The crystal structures of the PTP-MEG2-inhibitor complexes provide direct evidence that potent and selective PTP inhibitors can be obtained by introducing molecular diversity into the F(2)Pmp scaffold to engage both the active site and unique nearby peripheral binding pockets. Importantly, the PTP-MEG2 inhibitor possesses highly efficacious cellular activity and is capable of augmenting insulin signaling and improving insulin sensitivity and glucose homeostasis in diet-induced obese mice. The results indicate that F(2)Pmp can be converted into highly potent and selective PTP inhibitory agents with excellent in vivo efficacy. Given the general nature of the approach, this strategy should be applicable to other members of the PTP superfamily.