PDBsum entry 1gfy

Hydrolase

PDB id: 1gfy

Contents

Protein chain

296 a.a. *

Ligands

COL

Waters ×209

* Residue conservation analysis

PDB id:

1gfy

Name:

Hydrolase

Title:

Residue 259 is a key determinant of substrate specificity of protein- tyrosine phosphatase 1b and alpha

Structure:

Protein (protein-tyrosine phosphatase 1b). Chain: a. Fragment: catalytic domain. Synonym: ptp1b. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.13Å R-factor: 0.191 R-free: 0.250

Authors:

L.F.Iversen

Key ref:

G.H.Peters et al. (2000). Residue 259 is a key determinant of substrate specificity of protein-tyrosine phosphatases 1B and alpha. J Biol Chem, 275, 18201-18209. PubMed id: 10748206 DOI: 10.1074/jbc.M910273199

Date:

26-Jun-00 Release date: 04-Jul-00

Protein chain

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

Seq: 435 a.a.

Struc: 296 a.a.*

* PDB and UniProt seqs differ at 6 residue positions (black crosses)

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.M910273199

J Biol Chem 275:18201-18209 (2000)

PubMed id: 10748206

Residue 259 is a key determinant of substrate specificity of protein-tyrosine phosphatases 1B and alpha.

G.H.Peters, L.F.Iversen, S.Branner, H.S.Andersen, S.B.Mortensen, O.H.Olsen, K.B.Moller, N.P.Moller.

ABSTRACT

The aim of this study was to define the structural elements that determine the differences in substrate recognition capacity of two protein-tyrosine phosphatases (PTPs), PTP1B and PTPalpha, both suggested to be negative regulators of insulin signaling. Since the Ac-DADE(pY)L-NH(2) peptide is well recognized by PTP1B, but less efficiently by PTPalpha, it was chosen as a tool for these analyses. Calpha regiovariation analyses and primary sequence alignments indicate that residues 47, 48, 258, and 259 (PTP1B numbering) define a selectivity-determining region. By analyzing a set of DADE(pY)L analogs with a series of PTP mutants in which these four residues were exchanged between PTP1B and PTPalpha, either in combination or alone, we here demonstrate that the key selectivity-determining residue is 259. In PTPalpha, this residue is a glutamine causing steric hindrance and in PTP1B a glycine allowing broad substrate recognition. Significantly, replacing Gln(259) with a glycine almost turns PTPalpha into a PTP1B-like enzyme. By using a novel set of PTP inhibitors and x-ray crystallography, we further provide evidence that Gln(259) in PTPalpha plays a dual role leading to restricted substrate recognition (directly via steric hindrance) and reduced catalytic activity (indirectly via Gln(262)). Both effects may indicate that PTPalpha regulates highly selective signal transduction processes.

Selected figure(s)

Figure 1.
Fig. 1. Chemical structures of compounds 1-4.

Figure 7.
Fig. 7. Schematic presentation of the catalytic reaction showing the proposed effects of the side chain Gln259.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2000, 275, 18201-18209) copyright 2000.

Figures were selected by an automated process.