PDBsum entry 1pxh

Hydrolase

PDB id: 1pxh

Contents

Protein chain

297 a.a. *

Ligands

SNA

ACY ×2

Metals

_MG ×2

Waters ×109

* Residue conservation analysis

PDB id:

1pxh

Name:

Hydrolase

Title:

Crystal structure of protein tyrosine phosphatase 1b with potent and selective bidentate inhibitor compound 2

Structure:

Protein-tyrosine phosphatase, non-receptor type 1. Chain: a. Fragment: residues 1-321. Synonym: protein-tyrosine phosphatase 1b, ptp-1b. Engineered: yes

Source:

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

Resolution:

2.15Å R-factor: 0.200 R-free: 0.207

Authors:

J.P.Sun,A.Fedorov,S.Y.Lee,X.L.Guo,K.Shen,D.S.Lawrence,S.C.Almo, Z.Y.Zhang

Key ref:

J.P.Sun et al. (2003). Crystal structure of PTP1B complexed with a potent and selective bidentate inhibitor. J Biol Chem, 278, 12406-12414. PubMed id: 12547827 DOI: 10.1074/jbc.M212491200

Date:

04-Jul-03 Release date: 12-Aug-03

Supersedes:

1n6w

Protein chain

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

Seq: 435 a.a.

Struc: 297 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.M212491200

J Biol Chem 278:12406-12414 (2003)

PubMed id: 12547827

Crystal structure of PTP1B complexed with a potent and selective bidentate inhibitor.

J.P.Sun, A.A.Fedorov, S.Y.Lee, X.L.Guo, K.Shen, D.S.Lawrence, S.C.Almo, Z.Y.Zhang.

ABSTRACT

Protein-tyrosine phosphatase 1B (PTP1B) has been implicated as an important regulator in several signaling pathways including those initiated by insulin and leptin. Potent and specific PTP1B inhibitors could serve as useful tools in elucidating the physiological functions of PTP1B and may constitute valuable therapeutics in the treatment of several human diseases. We have determined the crystal structure of PTP1B in complex with compound 2, the most potent and selective PTP1B inhibitor reported to date. The structure at 2.15-A resolution reveals that compound 2 simultaneously binds to the active site and a unique proximal noncatalytic site formed by Lys-41, Arg-47, and Asp-48. The structural data are further corroborated by results from kinetic analyses of the interactions of PTP1B and its site-directed mutants with compound 2 and several of its variants. Although many of the residues important for interactions between PTP1B and compound 2 are not unique to PTP1B, the combinations of all contact residues differ between PTP isozymes, which provide a structural basis for potent and selective PTP1B inhibition. Our data further suggest that potent, yet highly selective, PTP1B inhibitory agents can be acquired by targeting the area defined by residues Lys-41, Arg-47, and Asp-48, in addition to the previously identified second aryl phosphate-binding pocket.

Selected figure(s)

Figure 4.
Fig. 4. Interactions between 2 and PTP1B. a, H-bonding (blue dotted lines) and polar interactions (red dotted lines); b, hydrophobic interactions (orange dotted lines), and; c, interactions between the two fluorine atoms in F[2]Pmp and PTP1B. The cut-off distance used is 3.2 Å for hydrogen bonds, 4.0 Å for electrostatic or polar interactions, and 4.5 Å for hydrophobic interactions.

Figure 5.
Fig. 5. Interactions of Arg-47 and Lys-41 with the EGFR peptide (a), the PTP1B consensus peptide (b), compound 2 (c), and compound 4 (d). Hydrophobic interactions are indicated by orange dotted lines, H-bonds by blue dotted lines, and polar interactions by red dotted lines.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 12406-12414) copyright 2003.

Figures were selected by an automated process.