1lqf

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spinqualitylabelsall models PDB ID 1lqf Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image
, resolution 2.5Å
Ligands:
Activity:	Protein-tyrosine-phosphatase, with EC number 3.1.3.48
Coordinates:	save as pdb, mmCIF, xml

Structure of PTP1b in Complex with a Peptidic Bisphosphonate Inhibitor

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Inhibitors of PTP-1B could be therapeutically beneficial in the treatment of type 2 diabetes. Owing to the large number of phosphatases in the cell, inhibitors against PTP-1B must not only be potent but selective as well. N-Benzoyl-L-glutamyl-[4-phosphono(difluoromethyl)]-L-phenylalanine-[4-phos phono(difluoro-methyl)]-L-phenylalanineamide (BzN-EJJ-amide) is a low nanomolar inhibitor of PTP-1B that shows selectivity over several protein tyrosine phosphatases. To gain an insight into the basis of its potency and selectivity, we evaluated several analogues of the inhibitor and introduced amino acid substitutions into PTP-1B by site-directed mutagenesis. We also determined the crystal structure of PTP-1B in complex with BzN-EJJ-amide at 2.5 A resolution. Our results indicate that the high inhibitory potency is due to interactions of several of its chemical groups with specific protein residues. An interaction between BzN-EJJ-amide and Asp48 is of particular significance, as substitution of Asp48 to alanine resulted in a 100-fold loss in potency. The crystal structure also revealed an unexpected binding orientation for a bisphosphonate inhibitor on PTP-1B, where the second difluorophosphonomethyl phenylalanine (F(2)PMP) moiety is bound close to Arg47 rather than in the previously identified second aryl phosphate site demarked by Arg24 and Arg254. Our results suggest that potent and selective PTP-1B inhibitors may be designed by targeting the region containing Arg47 and Asp48.

Disease

Known diseases associated with this structure: Abdominal body fat distribution, modifier of OMIM:[176885], Insulin resistance, susceptibility to OMIM:[176885]

About this Structure

1LQF is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

The structure of PTP-1B in complex with a peptide inhibitor reveals an alternative binding mode for bisphosphonates., Asante-Appiah E, Patel S, Dufresne C, Roy P, Wang Q, Patel V, Friesen RW, Ramachandran C, Becker JW, Leblanc Y, Kennedy BP, Scapin G, Biochemistry. 2002 Jul 23;41(29):9043-51. PMID:12119018

Page seeded by OCA on Thu Mar 20 12:33:56 2008