4j51

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

spinqualitylabelsall models 4j51, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4j51 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.3Å Ligands: N75 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease PTN22_HUMAN Defects in PTPN22 are a cause of susceptibility to systemic lupus erythematosus (SLE) [MIM:152700. SLE is a chronic, inflammatory and often febrile multisystemic disorder of connective tissue. It affects principally the skin, joints, kidneys and serosal membranes. It is thought to represent a failure of the regulatory mechanisms of the autoimmune system. Function PTN22_HUMAN Acts as negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signaling molecules. Associates with and probably dephosphorylates CBL. Dephosphorylates LCK at its activating 'Tyr-394' residue. Dephosphorylates ZAP70 at its activating 'Tyr-493' residue. Dephosphorylates the immune system activator SKAP2. Publication Abstract from PubMed 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 Ki 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. A Potent and Selective Small-Molecule Inhibitor for the Lymphoid-Specific Tyrosine Phosphatase (LYP), a Target Associated with Autoimmune Diseases.,He Y, Liu S, Menon A, Stanford S, Oppong E, Gunawan AM, Wu L, Wu DJ, Barrios AM, Bottini N, Cato AC, Zhang ZY J Med Chem. 2013 Jun 27;56(12):4990-5008. doi: 10.1021/jm400248c. Epub 2013 Jun, 6. PMID:23713581 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Tyrosine phosphatase 3D structures

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