PDBsum entry 2fjm

Hydrolase

PDB id: 2fjm

Contents

Protein chains

285 a.a. *

Ligands

073 ×2

Metals

_CL ×2

_MG

Waters ×299

* Residue conservation analysis

PDB id:

2fjm

Name:

Hydrolase

Title:

The structure of phosphotyrosine phosphatase 1b in complex with compound 2

Structure:

Tyrosine-protein phosphatase, non-receptor type 1. Chain: a, b. Fragment: catalytic domain (residues 1-298). Synonym: protein-tyrosine phosphatase 1b, ptp-1b. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ptpn1, ptp1b. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.10Å R-factor: 0.193 R-free: 0.217

Authors:

E.Asante-Appiah,S.Patel,C.Desponts,J.M.Taylor,C.Lau,C.Dufresne, M.Therien,R.Friesen,J.W.Becker,Y.Leblanc,G.Scapin

Key ref:

E.Asante-Appiah et al. (2006). Conformation-assisted inhibition of protein-tyrosine phosphatase-1B elicits inhibitor selectivity over T-cell protein-tyrosine phosphatase. J Biol Chem, 281, 8010-8015. PubMed id: 16407290 DOI: 10.1074/jbc.M511827200

Date:

03-Jan-06 Release date: 17-Jan-06

Protein chains

P18031  (PTN1_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 1 from Homo sapiens

Seq: 435 a.a.

Struc: 285 a.a.

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

DOI no: 10.1074/jbc.M511827200

J Biol Chem 281:8010-8015 (2006)

PubMed id: 16407290

Conformation-assisted inhibition of protein-tyrosine phosphatase-1B elicits inhibitor selectivity over T-cell protein-tyrosine phosphatase.

E.Asante-Appiah, S.Patel, C.Desponts, J.M.Taylor, C.Lau, C.Dufresne, M.Therien, R.Friesen, J.W.Becker, Y.Leblanc, B.P.Kennedy, G.Scapin.

ABSTRACT

PTP-1B represents an attractive target for the treatment of type 2 diabetes and obesity. Given the role that protein phosphatases play in the regulation of many biologically relevant processes, inhibitors against PTP-1B must be not only potent, but also selective. It has been extremely difficult to synthesize inhibitors that are selective over the highly homologous TCPTP. We have successfully exploited the conservative Leu119 to Val substitution between the two enzymes to synthesize a PTP-1B inhibitor that is an order of magnitude more selective over TCPTP. Structural analyses of PTP-1B/inhibitor complexes show a conformation-assisted inhibition mechanism as the basis for selectivity. Such an inhibitory mechanism may be applicable to other homologous enzymes.

Selected figure(s)

Figure 1.
Chemical structures and IC[50]s for compound 1 and its analog, compound 2 (without the ester group), on PTP-1B and TCPTP.

Figure 2.
A, representation of compound 1 bound in WT PTP-1B binding site: red, P-loop or catalytic site (His^214-Arg^221); magenta, WPD loop (His^175-Pro^185), containing the catalytic Asp^181; yellow, YRD loop (Tyr^46-Asp^48); blue, secondary aryl binding site, including Arg^24 and Arg^254, as described by Puius et al. (16). The loop spanning residues 110-121 is colored according to atom type (C, green;N, blue;O, red;S, yellow); the residues that are different in PTP-1B and TCPTP are in orange. B, stereo-view of the overlay of compound 1 and the 110-121 loops in the two molecules present in the asymmetric unit (green and yellow). Although the conformation of the loops are somewhat different, they both assume a closed conformation (i.e. near the bound ligand), and the side chain of Leu^119 is in both molecules interacting with the ligand. The position of the same loop in 1PTY (magenta) is also displayed for comparison.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2006, 281, 8010-8015) copyright 2006.

Figures were selected by an automated process.