Crystal Structure of PTP1B Complexed with a Potent and Selective Bidentate Inhibitor

Sun, Jin Peng; Fedorov, A.A.; Lee, Seung Yub; Guo, Xiaoyi; Shen, Kui; Lawrence, David S.; Almo, Steven C.; Zhang, Zhong Yin

doi:10.1074/jbc.m212491200

Cited by 142 publications

(153 citation statements)

References 44 publications

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“…In this context, it is of interest that an elegant study demonstrated that Arg-47 can adopt one of two conformations and thus accommodate different substrates that bind to this part of PTP1B. Indeed, several PTP1B inhibitors have been shown to address Arg-47 (18,22).…”

Section: Discussionmentioning

confidence: 99%

“…However, in this case molecular modeling indicated that position 5 in OATP would be more attractive for introducing substituents that could address the region defined by residues 47 and 48. Of note, a highly selective and potent PTP1B inhibitor that simultaneous binds to the active site and both residues was recently described (22). Therefore, our goal was to introduce substituents into OATP that would bind PTP␤ with high affinity and PTP1B with lower affinity.…”

Section: Discussionmentioning

confidence: 99%

“…3, 13, and 14), and several research groups have successfully used structure-based designs to synthesize active site-directed, selective PTP1B inhibitors (15)(16)(17)(18)(19)(20). Most important, two groups have demonstrated recently that it is possible to develop compounds that are selective for PTP1B over the highly homologous T cell-PTP (21,22), thereby lending support to the view that selective inhibitors, which discriminate between even closely related PTPs, are within reach.…”

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confidence: 99%

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Structure-based Design of Selective and Potent Inhibitors of Protein-tyrosine Phosphatase β

Lund

Andersen

Iversen

et al. 2004

Journal of Biological Chemistry

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Protein-tyrosine phosphatases (PTPs) are considered important therapeutic targets because of their pivotal role as regulators of signal transduction and thus their implication in several human diseases such as diabetes, cancer, and autoimmunity. In particular, PTP1B has been the focus of many academic and industrial laboratories because it was found to be an important negative regulator of insulin and leptin signaling, and hence a potential therapeutic target in diabetes and obesity. As a result, significant progress has been achieved in the design of highly selective and potent PTP1B inhibitors. In contrast, little attention has been given to other potential drug targets within the PTP family. Guided by x-ray crystallography, molecular modeling, and enzyme kinetic analyses with wild type and mutant PTPs, we describe the development of a general, low molecular weight, non-peptide, non-phosphorus PTP inhibitor into an inhibitor that displays more than 100-fold selectivity for PTP␤ over PTP1B. Of note, our structure-based design principles, which are based on extensive bioinformatics analyses of the PTP family, are general in nature. Therefore, we anticipate that this strategy, here applied to PTP␤, in principle can be used in the design and development of selective inhibitors of many, if not most PTPs.Protein-tyrosine phosphatases (PTPs) 1 are key regulators of signal transduction. Together with the counteracting proteintyrosine kinases, they control the phosphorylation status of many important proteins and are thereby critically involved in the regulation of fundamental cellular processes such as metabolism, cell growth, and differentiation. Aberrant tyrosine phosphorylation levels have been associated with the development of cancer, autoimmunity, and diabetes, thus indicating that PTPs might play important etiological and pathogenic roles in these diseases (1-5). In particular, two elegant studies with PTP1B knockout mice, in which increased insulin sensitivity and resistance to diet-induced obesity were observed (6, 7), indicated that PTP1B is an important negative regulator of insulin and leptin action, suggesting that inhibition of this enzyme could augment and prolong insulin and leptin signaling (8, 9). As a result, a number of academic and industrial laboratories have devoted considerable efforts toward the development of selective inhibitors of PTP1B for treatment of type 2 diabetes and obesity resulting in very significant progress (reviewed in Refs. 10 -12). The field has advanced significantly by a number of x-ray crystallographic structures (reviewed in Refs. 3, 13, and 14), and several research groups have successfully used structure-based designs to synthesize active site-directed, selective PTP1B inhibitors (15-20). Most important, two groups have demonstrated recently that it is possible to develop compounds that are selective for PTP1B over the highly homologous T cell-PTP (21, 22), thereby lending support to the view that selective inhibitors, which discriminate between even closely related PTP...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Structure-based Design of Selective and Potent Inhibitors of Protein-tyrosine Phosphatase β

Lund

Andersen

Iversen

et al. 2004

Journal of Biological Chemistry

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“…Phosphatase Assay-Initial rate measurements for the Lypcatalyzed p-nitrophenyl phosphate hydrolysis were carried out as described (22,23). The Lyp-catalyzed hydrolysis of Tyr(P)-containing peptides was continuously monitored at 305 nm for the increase in tyrosine fluorescence with excitation at 280 nm (18 Peptide Synthesis and Characterization-The synthesis and characterization of the inverse alanine phosphopeptide library were described previously (18).…”

Section: Methodsmentioning

confidence: 99%

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

Yu¹,

Chen²,

Zhang

et al. 2011

Journal of Biological Chemistry

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A missense single-nucleotide polymorphism in the gene encoding the lymphoid-specific tyrosine phosphatase (Lyp) has been identified as a causal factor in a wide spectrum of autoimmune diseases. Interestingly, the autoimmune-predisposing variant of Lyp appears to represent a gain-of-function mutation, implicating Lyp as an attractive target for the development of effective strategies for the treatment of many autoimmune disorders. Unfortunately, the precise biological functions of Lyp in signaling cascades and cellular physiology are poorly understood. Identification and characterization of Lyp substrates will help define the chain of molecular events coupling Lyp dysfunction to diseases. In the current study, we identified consensus sequence motifs for Lyp substrate recognition using an "inverse alanine scanning" combinatorial library approach. The intrinsic sequence specificity data led to the discovery and characterization of SKAP-HOM, a cytosolic adaptor protein required for proper activation of the immune system, as a bona fide Lyp substrate. To determine the molecular basis for Lyp substrate recognition, we solved crystal structures of Lyp in complex with the consensus peptide as well as the phosphopeptide derived from SKAP-HOM. Together with the biochemical data, the structures define the molecular determinants for Lyp substrate specificity and provide a solid foundation upon which novel therapeutics targeting Lyp can be developed for multiple autoimmune diseases.Protein-tyrosine phosphorylation-mediated signal transduction is essential for a wide range of eukaryotic functions, including cell proliferation, differentiation, migration, apoptosis, and the immune responses (1). This signaling mechanism is often dysregulated in human diseases, due to aberrant activity of the enzymes involved in the regulation of protein tyrosine phosphorylation status (1, 2). Thus, a comprehensive understanding of the physiological roles of protein tyrosine phosphorylation and how this process is abrogated in the pathogenesis of human diseases must necessarily include characterization of proteintyrosine phosphatases (PTPs), 4 in addition to protein-tyrosine kinases.The lymphoid-specific tyrosine phosphatase (Lyp) has garnered tremendous interest due to the observation that a missense C1858T single nucleotide polymorphism in the gene (PTPN22) encoding Lyp is associated with multiple autoimmune disorders, including type I diabetes (3), rheumatoid arthritis (4, 5), Graves disease (6), and systemic lupus erythematosus (7). Lyp expression is restricted to human T cells, B cells, and macrophages (8). Lyp exerts an inhibitory effect on the proximal T cell receptor signaling pathways, probably through dephosphorylation of the Lck and ZAP-70 kinases (9 -11). The C1858T single nucleotide polymorphism changes Arg 620 into a Trp within the first Pro-rich region in the C terminus of Lyp, leading to loss of Lyp binding to the Src homology 3 domain of the Src C-terminal kinase (Csk) (3, 4). Importantly, the autoimmune-predisposing variant of...

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“…The x-ray structure of PTP1B bound to an effective competitive inhibitor [Protein Data Bank (PDB) ID code 1N6W (27)] was used as a template. In the resulting model of Shp2, the active center appears as a deep and narrow substrate-binding pocket (Fig.…”

Section: Identification Of the Phps Compound Class Of Shp2 Inhibitorsmentioning

confidence: 99%

Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking

Hellmuth

Grosskopf

Lum

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

204

182

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The protein tyrosine phosphatase Shp2 is a positive regulator of growth factor signaling. Gain-of-function mutations in several types of leukemia define Shp2 as a bona fide oncogene. We performed a high-throughput in silico screen for small-molecular-weight compounds that bind the catalytic site of Shp2. We have identified the phenylhydrazonopyrazolone sulfonate PHPS1 as a potent and cellpermeable inhibitor, which is specific for Shp2 over the closely related tyrosine phosphatases Shp1 and PTP1B. PHPS1 inhibits Shp2-dependent cellular events such as hepatocyte growth factor/scatter factor (HGF/SF)-induced epithelial cell scattering and branching morphogenesis. PHPS1 also blocks Shp2-dependent downstream signaling, namely HGF/SF-induced sustained phosphorylation of the Erk1/2 MAP kinases and dephosphorylation of paxillin. Furthermore, PHPS1 efficiently inhibits activation of Erk1/2 by the leukemia-associated Shp2 mutant, Shp2-E76K, and blocks the anchorage-independent growth of a variety of human tumor cell lines. The PHPS compound class is therefore suitable for further development of therapeutics for the treatment of Shp2-dependent diseases.chemical biology ͉ growth factor signaling ͉ phosphatase inhibition ͉ virtual drug screening

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Crystal Structure of PTP1B Complexed with a Potent and Selective Bidentate Inhibitor

Cited by 142 publications

References 44 publications

Structure-based Design of Selective and Potent Inhibitors of Protein-tyrosine Phosphatase β

Structure-based Design of Selective and Potent Inhibitors of Protein-tyrosine Phosphatase β

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

Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking

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