4J51

Cyrstal structure of protein tyrosine phosphatase Lyp catalytic domain complex with small molecular inhibitor L75N04

Summary for 4J51

• Entry DOI: 10.2210/pdb4j51/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 22, 3-[(3-chlorophenyl)ethynyl]-2-{4-[2-(cyclopropylamino)-2-oxoethoxy]phenyl}-6-hydroxy-1-benzofuran-5-carboxylic acid (3 entities in total)
• Functional Keywords: hydrolase, tyrosine phosphatase, inhibitor design, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm (By similarity): Q9Y2R2
• Total number of polymer chains: 2
• Total formula weight: 77269.10

Authors

Liu, D.,He, Y.,Zhang, Z.-Y. (deposition date: 2013-02-07, release date: 2013-07-24, Last modification date: 2023-09-20)

Primary citation

He, Y.,Liu, S.,Menon, A.,Stanford, S.,Oppong, E.,Gunawan, A.M.,Wu, L.,Wu, D.J.,Barrios, A.M.,Bottini, N.,Cato, A.C.,Zhang, Z.Y.
A Potent and Selective Small-Molecule Inhibitor for the Lymphoid-Specific Tyrosine Phosphatase (LYP), a Target Associated with Autoimmune Diseases.
J.Med.Chem., 56:4990-5008, 2013

PubMed Abstract: Lymphoid-specific tyrosine phosphatase (LYP), a member of the protein tyrosine phosphatase (PTP) family of signaling enzymes, is associated with a broad spectrum of autoimmune diseases. Herein we describe our structure-based lead optimization efforts within a 6-hydroxy-benzofuran-5-carboxylic acid series culminating in the identification of compound 8b, a potent and selective inhibitor of LYP with a K(i) value of 110 nM and more than 9-fold selectivity over a large panel of PTPs. The structure of LYP in complex with 8b was obtained by X-ray crystallography, providing detailed information about the molecular recognition of small-molecule ligands binding LYP. Importantly, compound 8b possesses highly efficacious cellular activity in both T- and mast cells and is capable of blocking anaphylaxis in mice. Discovery of 8b establishes a starting point for the development of clinically useful LYP inhibitors for treating a wide range of autoimmune disorders.

PubMed: 23713581
DOI: 10.1021/jm400248c

Experimental method

X-RAY DIFFRACTION (2.3 Å)