PDBsum entry 1kav

Hydrolase

PDB id: 1kav

Contents

Protein chain

297 a.a. *

Ligands

FEP

Waters ×133

* Residue conservation analysis

PDB id:

1kav

Name:

Hydrolase

Title:

Human tyrosine phosphatase 1b complexed with an inhibitor

Structure:

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

Source:

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

Resolution:

2.35Å R-factor: 0.200 R-free: 0.250

Authors:

Z.Jia,Q.Ye,A.N.Dinaut,Q.Wang,D.Waddleton,P.Payette,C.Ramachandran, B.Kennedy,G.Hum,S.D.Taylor

Key ref:

Z.Jia et al. (2001). Structure of protein tyrosine phosphatase 1B in complex with inhibitors bearing two phosphotyrosine mimetics. J Med Chem, 44, 4584-4594. PubMed id: 11741477 DOI: 10.1021/jm010266w

Date:

03-Nov-01 Release date: 19-Jun-02

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: 10.1021/jm010266w

J Med Chem 44:4584-4594 (2001)

PubMed id: 11741477

Structure of protein tyrosine phosphatase 1B in complex with inhibitors bearing two phosphotyrosine mimetics.

Z.Jia, Q.Ye, A.N.Dinaut, Q.Wang, D.Waddleton, P.Payette, C.Ramachandran, B.Kennedy, G.Hum, S.D.Taylor.

ABSTRACT

Protein tyrosine phosphatases (PTPases) are signal-transducing enzymes that dephosphorylate intracellular proteins that have phosphorylated tyrosine residues. It has been demonstrated that protein tyrosine phosphatase 1B (PTP1B) is an attractive therapeutic target because of its involvement in regulating insulin sensitivity (Elcheby et al. Science 1999, 283, 1544-1548). The identification of a second binding site in PTP1B (Puius et al., Proc. Natl. Acad. Sci. U.S.A.1997, 94, 13420-13425) suggests a new strategy for inhibitor design, where appropriate compounds may be made to simultaneously occupy both binding sites to gain much higher affinity and selectivity. To test this hypothesis and gain further insights into the structural basis of inhibitor binding, we have determined the crystal structure of PTP1B complexed with two non-peptidyl inhibitors, 4 and 5, both of which contain two aryl difluoromethylenephosphonic acid groups, a nonhydrolyzable phosphate mimetic. The structures were determined and refined to 2.35 and 2.50 A resolution, respectively. Although one of the inhibitors seems to have satisfied the perceived requirement for dual binding, it did not bind both the active site and the adjacent noncatalytic binding site as expected. The second or distal phosphonate group instead extends into the solvent and makes water-mediated interactions with Arg-47. The selectivity of the more potent of these two inhibitors, as well as four other inhibitors bearing two such phosphate mimetics for PTP1B versus seven other PTPases, was examined. In general, selectivity was modest to good when compared to PTPases Cdc25a, PTPmeg-1, PTPbeta, and CD45. However, selectivity was generally poor when compared to other PTPases such as SHP-1, SHP-2, and especially TCPTP, for which almost no selectivity was found. The implications these results have concerning the utility of dual-binding inhibitors are discussed.