1t49

Allosteric Inhibition of Protein Tyrosine Phosphatase 1B

spinqualitylabelsall models 1t49, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1t49 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 892, MG Related: 1pty, 2hnp, 1t48, 1t4j Gene: PTPN1, PTP1B (Homo sapiens) Activity: Protein-tyrosine-phosphatase, with EC number 3.1.3.48 Resources: FirstGlance, OCA, RCSB, PDBsum Function [PTN1_HUMAN] Tyrosine-protein phosphatase which acts as a regulator of endoplasmic reticulum unfolded protein response. Mediates dephosphorylation of EIF2AK3/PERK; inactivating the protein kinase activity of EIF2AK3/PERK. May play an important role in CKII- and p60c-src-induced signal transduction cascades. May regulate the EFNA5-EPHA3 signaling pathway which modulates cell reorganization and cell-cell repulsion. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Obesity and type II diabetes are closely linked metabolic syndromes that afflict >100 million people worldwide. Although protein tyrosine phosphatase 1B (PTP1B) has emerged as a promising target for the treatment of both syndromes, the discovery of pharmaceutically acceptable inhibitors that bind at the active site remains a substantial challenge. Here we describe the discovery of an allosteric site in PTP1B. Crystal structures of PTP1B in complex with allosteric inhibitors reveal a novel site located approximately 20 A from the catalytic site. We show that allosteric inhibitors prevent formation of the active form of the enzyme by blocking mobility of the catalytic loop, thereby exploiting a general mechanism used by tyrosine phosphatases. Notably, these inhibitors exhibit selectivity for PTP1B and enhance insulin signaling in cells. Allosteric inhibition is a promising strategy for targeting PTP1B and constitutes a mechanism that may be applicable to other tyrosine phosphatases. Allosteric inhibition of protein tyrosine phosphatase 1B.,Wiesmann C, Barr KJ, Kung J, Zhu J, Erlanson DA, Shen W, Fahr BJ, Zhong M, Taylor L, Randal M, McDowell RS, Hansen SK Nat Struct Mol Biol. 2004 Aug;11(8):730-7. Epub 2004 Jul 18. PMID:15258570 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Tyrosine phosphatase

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