PDBsum entry 3eb1

Hydrolase

PDB id: 3eb1

Contents

Protein chain

283 a.a. *

Ligands

LZQ

Waters ×157

* Residue conservation analysis

PDB id:

3eb1

Name:

Hydrolase

Title:

Crystal structure ptp1b complex with small molecule inhibitor lzp-25

Structure:

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

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ptpn1, ptp1b. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.40Å R-factor: 0.207 R-free: 0.253

Authors:

S.Liu,L.-F.Zheng,L.Wu,X.Yu,T.Xue,A.M.Gunawan,Y.-Q.Long,Z.-Y.Zhang

Key ref:

S.Liu et al. (2008). Targeting inactive enzyme conformation: aryl diketoacid derivatives as a new class of PTP1B inhibitors. J Am Chem Soc, 130, 17075-17084. PubMed id: 19012396

Date:

26-Aug-08 Release date: 07-Jul-09

Protein chain

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

Seq: 435 a.a.

Struc: 283 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

J Am Chem Soc 130:17075-17084 (2008)

PubMed id: 19012396

Targeting inactive enzyme conformation: aryl diketoacid derivatives as a new class of PTP1B inhibitors.

S.Liu, L.F.Zeng, L.Wu, X.Yu, T.Xue, A.M.Gunawan, Y.Q.Long, Z.Y.Zhang.

ABSTRACT

There has been considerable interest in protein tyrosine phosphatase 1B (PTP1B) as a therapeutic target for diabetes, obesity, as well as cancer. Identifying inhibitory compounds with good bioavailability is a major challenge of drug discovery programs targeted toward PTPs. Most current PTP active site-directed pharmacophores are negatively charged pTyr mimetics which cannot readily enter the cell. This lack of cell permeability limits the utility of such compounds in signaling studies and further therapeutic development. We identify aryl diketoacids as novel pTyr surrogates and show that neutral amide-linked aryl diketoacid dimers also exhibit excellent PTP inhibitory activity. Kinetic studies establish that these aryl diketoacid derivatives act as noncompetitive inhibitors of PTP1B. Crystal structures of ligand-bound PTP1B reveal that both the aryl diketoacid and its dimeric derivative bind PTP1B at the active site, albeit with distinct modes of interaction, in the catalytically inactive, WPD loop open conformation. Furthermore, dimeric aryl diketoacids are cell permeable and enhance insulin signaling in hepatoma cells, suggesting that targeting the inactive conformation may provide a unique opportunity for creating active site-directed PTP1B inhibitors with improved pharmacological properties.