4j51

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

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.[1]

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.[2] [3] [4] [5]

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[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
7 reviews cite this structure
Protein tyrosine phosphatases as potential therapeutic targets.
He et al. (2014)
6 more
16 other articles
No citations found

See Also

References

  1. ↑ Kyogoku C, Langefeld CD, Ortmann WA, Lee A, Selby S, Carlton VE, Chang M, Ramos P, Baechler EC, Batliwalla FM, Novitzke J, Williams AH, Gillett C, Rodine P, Graham RR, Ardlie KG, Gaffney PM, Moser KL, Petri M, Begovich AB, Gregersen PK, Behrens TW. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet. 2004 Sep;75(3):504-7. Epub 2004 Jul 23. PMID:15273934 doi:10.1086/423790
  2. ↑ Wu J, Katrekar A, Honigberg LA, Smith AM, Conn MT, Tang J, Jeffery D, Mortara K, Sampang J, Williams SR, Buggy J, Clark JM. Identification of substrates of human protein-tyrosine phosphatase PTPN22. J Biol Chem. 2006 Apr 21;281(16):11002-10. Epub 2006 Feb 6. PMID:16461343 doi:10.1074/jbc.M600498200
  3. ↑ Yu X, Sun JP, He Y, Guo X, Liu S, Zhou B, Hudmon A, Zhang ZY. Structure, inhibitor, and regulatory mechanism of Lyp, a lymphoid-specific tyrosine phosphatase implicated in autoimmune diseases. Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19767-72. Epub 2007 Dec 3. PMID:18056643 doi:10.1073/pnas.0706233104
  4. ↑ Barr AJ, Ugochukwu E, Lee WH, King ON, Filippakopoulos P, Alfano I, Savitsky P, Burgess-Brown NA, Muller S, Knapp S. Large-scale structural analysis of the classical human protein tyrosine phosphatome. Cell. 2009 Jan 23;136(2):352-63. PMID:19167335 doi:http://dx.doi.org/10.1016/j.cell.2008.11.038
  5. ↑ Yu X, Chen M, Zhang S, Yu ZH, Sun JP, Wang L, Liu S, Imasaki T, Takagi Y, Zhang ZY. Substrate Specificity of Lymphoid-specific Tyrosine Phosphatase (Lyp) and Identification of Src Kinase-associated Protein of 55 kDa Homolog (SKAP-HOM) as a Lyp Substrate. J Biol Chem. 2011 Sep 2;286(35):30526-34. Epub 2011 Jun 30. PMID:21719704 doi:10.1074/jbc.M111.254722
  6. ↑ He Y, Liu S, Menon A, Stanford S, Oppong E, Gunawan AM, Wu L, Wu DJ, Barrios AM, Bottini N, Cato AC, Zhang ZY. A Potent and Selective Small-Molecule Inhibitor for the Lymphoid-Specific Tyrosine Phosphatase (LYP), a Target Associated with Autoimmune Diseases. J Med Chem. 2013 Jun 27;56(12):4990-5008. doi: 10.1021/jm400248c. Epub 2013 Jun, 6. PMID:23713581 doi:10.1021/jm400248c

Contents


PDB ID 4j51

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