共查询到20条相似文献,搜索用时 15 毫秒
1.
González-Rodriguez A Nevado C Escrivá F Sesti G Rondinone CM Benito M Valverde AM 《American journal of physiology. Gastrointestinal and liver physiology》2008,295(2):G338-G347
The contribution of the liver to glucose utilization is essential to maintain glucose homeostasis. Previous data from protein tyrosine phosphatase (PTP) 1B-deficient mice demonstrated that the liver is a major site for PTP1B action in the periphery. In this study, we have investigated the consequences of PTP1B deficiency in glucose uptake in hepatocytes from neonatal and adult mice. The lack of PTP1B increased basal glucose uptake in hepatocytes from neonatal (3-5 days old) but not adult (10-12 wk old) mice. This occurs without changes in hexokinase, glucokinase, and glucose 6-phosphatase enzymatic activities. By contrast, the glucose transporter GLUT2 was upregulated at the protein level in neonatal hepatocytes and livers from PTP1B-deficient neonates. These results were accompanied by a significant increase in the net free intrahepatic glucose levels in the livers of PTP1B(-/-) neonates. The association between GLUT2 and insulin receptor (IR) A isoform was increased in PTP1B(-/-) neonatal hepatocytes compared with the wild-type. Indeed, PTP1B deficiency in neonatal hepatocytes shifted the ratio of isoforms A and B of the IR by increasing the amount of IRA and decreasing IRB. Moreover, overexpression of IRA in PTP1B(-/-) neonatal hepatocytes increased the amount of IRA/GLUT2 complexes. Conversely, hepatocytes from adult mice only expressed IRB. Since IRA plays a direct role in the regulation of glucose uptake in neonatal hepatocytes through its specific association with GLUT2, we propose the increase in IRA/GLUT2 complexes due to PTP1B deficiency as the molecular mechanism of the increased glucose uptake in the neonatal stage. 相似文献
2.
3.
Liver-specific protein-tyrosine phosphatase 1B (PTP1B) re-expression alters glucose homeostasis of PTP1B-/-mice 总被引:17,自引:0,他引:17
Haj FG Zabolotny JM Kim YB Kahn BB Neel BG 《The Journal of biological chemistry》2005,280(15):15038-15046
Protein-tyrosine phosphatase 1B (PTP1B) is an important negative regulator of insulin and leptin signaling in vivo. Mice lacking PTP1B (PTP1B-/- mice) are hyper-responsive to insulin and leptin and resistant to diet-induced obesity. The tissue(s) that mediate these effects of global PTP1B deficiency remain controversial. We exploited the high degree of hepatotropism of adenoviruses to assess the role of PTP1B in the liver. Liver-specific re-expression of PTP1B in PTP1B-/- mice led to marked attenuation of their enhanced insulin sensitivity. This correlated with, and was probably caused by, decreased insulin-stimulated tyrosyl phosphorylation of the insulin receptor (IR) and IR substrate 2-associated phosphatidylinositide 3-kinase activity. Analysis using phospho-specific antibodies for the IR revealed preferential dephosphorylation of Tyr-1162/1163 compared with Tyr-972 by PTP1B in vivo. Our findings show that the liver is a major site of the peripheral action of PTP1B in regulating glucose homeostasis. 相似文献
4.
Protein tyrosine phosphatase 1B regulates TGF beta 1-induced Smad2 activation through PI3 kinase-dependent pathway 总被引:1,自引:0,他引:1
Insulin is known to modulate transforming growth factor-beta (TGFbeta) signaling. In this report, by using the IN Cell Analyzer 1000, the fluorescence cell imaging instrument, we demonstrated that protein tyrosine phosphatase 1B (PTP1B) could regulate TGFbeta1-induced Smad2 activation in a PI3 kinase-dependent manner. By using the CHO cells stably expressing EGFP-Smad2, we showed that TGFbeta1 effectively stimulated Smad2 nuclear translocation in CHO cells. When pretreated with insulin, TGFbeta1-induced Smad2 nuclear entry was dramatically decreased. Furthermore, both the PI3K inhibitor LY294002 and the dominant negative AKT (DN-AKT) abolished the inhibitory effects of insulin, demonstrating that the inhibition of Smad2 activation by insulin was PI3K/AKT dependent. Since PTP1B negatively modulates insulin signaling, we further addressed the effects of PTP1B on insulin-mediated inhibition of Smad2 activation. Our data showed that overexpression of PTP1B effectively attenuated insulin-induced inhibition of Smad2 stimulation. Moreover, the PTP1B inhibitor, 3-(3,5-dibromo-4-hydroxy-benzoyl)-2-ethyl-benzofuran-6-sulfonicacid-(4-(thiazol-2-ylsulfamyl)-phenyl)-amide (Compound-2), recovered insulin inhibition of Smad2 activation. In conclusion, our data revealed the insulin inhibitory effects on TGFbeta1-induced Smad2 activation and the regulation role of PTP1B in the inhibition events. 相似文献
5.
Na M Hoang DM Njamen D Mbafor JT Fomum ZT Thuong PT Ahn JS Oh WK 《Bioorganic & medicinal chemistry letters》2007,17(14):3868-3871
Bioassay-guided fractionation of an EtOAc-soluble extract of the stem bark of Erythrina addisoniae (Leguminosae), using an in vitro PTP1B inhibitory assay, resulted in the isolation of three new (1-3) and three known (4-6) 2-arylbenzofuran derivatives. The new compounds were identified as 2-[2',4'-dihydroxy-3'-(3-methylbut-2-enyl)phenyl]-6-hydroxybenzofuran (1), 2-[2'-methoxy-4'-hydroxy-5'-(3-methylbut-2-enyl)phenyl]-6-hydroxybenzofuran (2), and 2-(2'-methoxy-4'-hydroxyphenyl)-5-(3-methylbut-2-enyl)-6-hydroxybenzofuran (3). The new 2-arylbenzofurans 1-3 inhibited PTP1B activity with IC(50) values ranging from 13.6+/-1.1 to 17.5+/-1.2 microM in vitro assay. On the basis of the data obtained, 2-arylbenzofurans with prenyl group may be considered as a new class of PTP1B inhibitors. 相似文献
6.
Structural basis of plasticity in protein tyrosine phosphatase 1B substrate recognition 总被引:7,自引:0,他引:7
Sarmiento M Puius YA Vetter SW Keng YF Wu L Zhao Y Lawrence DS Almo SC Zhang ZY 《Biochemistry》2000,39(28):8171-8179
Protein tyrosine phosphatase 1B (PTP1B) displays a preference for peptides containing acidic as well as aromatic/aliphatic residues immediately NH(2)-terminal to phosphotyrosine. The structure of PTP1B bound with DADEpYL-NH(2) (EGFR(988)(-)(993)) offers a structural explanation for PTP1B's preference for acidic residues [Jia, Z., Barford, D., Flint, A. J., and Tonks, N. K. (1995) Science 268, 1754-1758]. We report here the crystal structures of PTP1B in complex with Ac-ELEFpYMDYE-NH(2) (PTP1B.Con) and Ac-DAD(Bpa)pYLIPQQG (PTP1B.Bpa) determined to 1.8 and 1.9 A resolution, respectively. A structural analysis of PTP1B.Con and PTP1B.Bpa shows how aromatic/aliphatic residues at the -1 and -3 positions of peptide substrates are accommodated by PTP1B. A comparison of the structures of PTP1B.Con and PTP1B.Bpa with that of PTP1B.EGFR(988)(-)(993) reveals the structural basis for the plasticity of PTP1B substrate recognition. PTP1B is able to bind phosphopeptides by utilizing common interactions involving the aromatic ring and phosphate moiety of phosphotyrosine itself, two conserved hydrogen bonds between the Asp48 carboxylate side chain and the main chain nitrogens of the pTyr and residue 1, and a third between the main chain nitrogen of Arg47 and the main chain carbonyl of residue -2. The ability of PTP1B to accommodate both acidic and hydrophobic residues immediately NH(2)-terminal to pTyr appears to be conferred upon PTP1B by a single residue, Arg47. Depending on the nature of the NH(2)-terminal amino acids, the side chain of Arg47 can adopt one of two different conformations, generating two sets of distinct peptide binding surfaces. When an acidic residue is positioned at position -1, a preference for a second acidic residue is also observed at position -2. However, when a large hydrophobic group occupies position -1, Arg47 adopts a new conformation so that it can participate in hydrophobic interactions with both positions -1 and -3. 相似文献
7.
Pedersen AK Branner S Mortensen SB Andersen HS Klausen KM Møller KB Møller NP Iversen LF 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2004,799(1):1-8
Our structure-based drug discovery program within the field of protein-tyrosine phosphatases (PTPs) demands delivery of significant amounts of protein with extraordinary purity specifications over prolonged time periods. Hence, replacement of classical, multi-step, low-yield protein purifications with efficient affinity techniques would be desirable. For this purpose, the highly selective PTP1B inhibitor 2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid (OTP) was coupled to epoxy-activated Sepharose 6B (OTP Sepharose) and used for one-step affinity purification of tag-free PTP1B. The elution was performed with a combined pH and salt gradient. Importantly, since OTP Sepharose binds PTP1B with an intact active site only, the method ensures that the purified enzyme is fully active, a feature that might be particularly important in PTP research. 相似文献
8.
Protein tyrosine phosphatase 1B (PTP1B) acts as a negative regulator of insulin and leptin signalling and is crucially involved in the development of type 2 diabetes mellitus, obesity, cancer and neurodegenerative diseases. Pursuing our efforts to identify PTP1B inhibitors endowed with drug-like properties, we designed and evaluated 3-aryl-5-arylidene-2-thioxo-4-imidazolidinones (7) as a novel class of non-carboxylate PTP1B inhibitors. In agreement with our design, kinetic studies demonstrated that selected compounds 7 act as reversible, non-competitive inhibitors of the target enzyme at low micromolar concentrations. Accordingly, molecular docking experiments suggested that these inhibitors can fit an allosteric site of PTP1B that we previously individuated. Moreover, cellular assays demonstrated that compound 7e acts as a potent insulin-sensitizing agent in human liver HepG2 cells. Taken together, our results showed that these non-competitive PTP1B inhibitors can be considered promising lead compounds aimed to enhance druggability of the target enzyme and identify novel antidiabetic drugs. 相似文献
9.
PTP1B regulates leptin signal transduction in vivo 总被引:15,自引:0,他引:15
Zabolotny JM Bence-Hanulec KK Stricker-Krongrad A Haj F Wang Y Minokoshi Y Kim YB Elmquist JK Tartaglia LA Kahn BB Neel BG 《Developmental cell》2002,2(4):489-495
Mice lacking the protein-tyrosine phosphatase PTP1B are hypersensitive to insulin and resistant to obesity. However, the molecular basis for resistance to obesity has been unclear. Here we show that PTP1B regulates leptin signaling. In transfection studies, PTP1B dephosphorylates the leptin receptor-associated kinase, Jak2. PTP1B is expressed in hypothalamic regions harboring leptin-responsive neurons. Compared to wild-type littermates, PTP1B(-/-) mice have decreased leptin/body fat ratios, leptin hypersensitivity, and enhanced leptin-induced hypothalamic Stat3 tyrosyl phosphorylation. Gold thioglucose treatment, which ablates leptin-responsive hypothalamic neurons, partially overcomes resistance to obesity in PTP1B(-/-) mice. Our data indicate that PTP1B regulates leptin signaling in vivo, likely by targeting Jak2. PTP1B may be a novel target to treat leptin resistance in obesity. 相似文献
10.
Liang F Lee SY Liang J Lawrence DS Zhang ZY 《The Journal of biological chemistry》2005,280(26):24857-24863
Protein-tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin and leptin signaling and a novel therapeutic target for the treatment of type 2 diabetes, obesity, and other associated metabolic syndromes. Because PTP1B regulates multiple signal pathways and it can both enhance and antagonize a cellular event, it is important to establish the physiological relevance of PTP1B in these processes. In this study, we utilize potent and selective PTP1B inhibitors to delineate the role of PTP1B in integrin signaling. We show that down-regulation of PTP1B activity with small molecule inhibitors suppresses cell spreading and migration to fibronectin, increases Tyr(527) phosphorylation in Src, and decreases phosphorylation of FAK, p130(Cas), and ERK1/2. In addition, PTP1B "substrate-trapping" mutants bind Tyr(527)-phosphorylated Src and protect it from dephosphorylation by endogenous PTP1B. These results establish that PTP1B promotes integrin-mediated responses in fibroblasts by dephosphorylating the inhibitory pTyr(527) and thereby activating the Src kinase. We also show that PTP1B forms a complex with Src and p130(Cas), and that the proline-rich motif PPRPPK (residues 309-314) in PTP1B is essential for the complex formation. We suggest that the specificity of PTP1B for Src pTyr(527) is mediated by protein-protein interactions involving the docking protein p130(Cas) with both Src and PTP1B in addition to the interactions between the PTP1B active site and the pTyr(527) motif. 相似文献
11.
Shuai Li Jingmiao Zhang Shaoyong Lu Wenkang Huang Lv Geng Qiancheng Shen Jian Zhang 《PloS one》2014,9(5)
As the prototypical member of the PTP family, protein tyrosine phosphatase 1B (PTP1B) is an attractive target for therapeutic interventions in type 2 diabetes. The extremely conserved catalytic site of PTP1B renders the design of selective PTP1B inhibitors intractable. Although discovered allosteric inhibitors containing a benzofuran sulfonamide scaffold offer fascinating opportunities to overcome selectivity issues, the allosteric inhibitory mechanism of PTP1B has remained elusive. Here, molecular dynamics (MD) simulations, coupled with a dynamic weighted community analysis, were performed to unveil the potential allosteric signal propagation pathway from the allosteric site to the catalytic site in PTP1B. This result revealed that the allosteric inhibitor compound-3 induces a conformational rearrangement in helix α7, disrupting the triangular interaction among helix α7, helix α3, and loop11. Helix α7 then produces a force, pulling helix α3 outward, and promotes Ser190 to interact with Tyr176. As a result, the deviation of Tyr176 abrogates the hydrophobic interactions with Trp179 and leads to the downward movement of the WPD loop, which forms an H-bond between Asp181 and Glu115. The formation of this H-bond constrains the WPD loop to its open conformation and thus inactivates PTP1B. The discovery of this allosteric mechanism provides an overall view of the regulation of PTP1B, which is an important insight for the design of potent allosteric PTP1B inhibitors. 相似文献
12.
Neuronal PTP1B regulates body weight, adiposity and leptin action 总被引:10,自引:0,他引:10
Bence KK Delibegovic M Xue B Gorgun CZ Hotamisligil GS Neel BG Kahn BB 《Nature medicine》2006,12(8):917-924
Obesity is a major health problem and a risk factor for type 2 diabetes. Leptin, an adipocyte-secreted hormone, acts on the hypothalamus to inhibit food intake and increase energy expenditure. Most obese individuals develop hyperleptinemia and leptin resistance, limiting the therapeutic efficacy of exogenously administered leptin. Mice lacking the tyrosine phosphatase PTP1B are protected from diet-induced obesity and are hypersensitive to leptin, but the site and mechanism for these effects remain controversial. We generated tissue-specific PTP1B knockout (Ptpn1(-/-)) mice. Neuronal Ptpn1(-/-) mice have reduced weight and adiposity, and increased activity and energy expenditure. In contrast, adipose PTP1B deficiency increases body weight, whereas PTP1B deletion in muscle or liver does not affect weight. Neuronal Ptpn1(-/-) mice are hypersensitive to leptin, despite paradoxically elevated leptin levels, and show improved glucose homeostasis. Thus, PTP1B regulates body mass and adiposity primarily through actions in the brain. Furthermore, neuronal PTP1B regulates adipocyte leptin production and probably is essential for the development of leptin resistance. 相似文献
13.
Levels of protein tyrosine phosphatase 1B determine susceptibility to apoptosis in serum-deprived hepatocytes 总被引:1,自引:0,他引:1
González-Rodriguez A Escribano O Alba J Rondinone CM Benito M Valverde AM 《Journal of cellular physiology》2007,212(1):76-88
Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of tyrosine kinase growth factor signaling. To assess the importance of PTP1B in the balance between death and survival in the liver, we have developed immortalized neonatal hepatocyte cell lines lacking (PTP1B(-/-)) or overexpressing (PTP1B(+/+PTP1B)) PTP1B. Early activation of caspase-3 occurred in PTP1B(+/+PTP1B) hepatocytes but was nearly abolished in PTP1B(-/-) cells. At the molecular level, PTP1B overexpression/deficiency altered the balance of pro-(Bim) and anti-(Bcl-x(L)) apoptotic members of the Bcl-2 family upon serum withdrawal. Likewise, cytosolic cytochrome C increased rapidly in PTP1B(+/+PTP1B) hepatocytes whereas it was retained in the mitochondria of PTP1B(-/-) cells. DNA fragmentation and the increase of apoptotic cells induced by serum withdrawal in wild-type (PTP1B(+/+)) hepatocytes were absent in PTP1B(-/-) cells. Conversely, overexpression of PTP1B accelerated DNA laddering and increased the number of apoptotic cells. In serum-deprived PTP1B(+/+PTP1B) hepatocytes, a rapid entry of Foxo1 into the nucleus and an earlier activation of caspase-8 was observed. However, both events were suppressed in PTP1B(-/-) hepatocytes. Moreover, PTP1B deficiency conferred resistance to apoptosis induced by activation of Fas and constitutively active Foxo1. Rescue of PTP 1B in deficient hepatocytes recovered the phenotype of wild-type cells whereas reduction of PTP1B by siRNA suppressed apoptosis. Our results reveal a unique role for PTP1B as a mediator of the apoptotic pathways triggered by trophic factors withdrawal in hepatocytes. This novel mechanism may represent an important target in the design of therapeutic strategies for human liver regeneration after pathological damage as well as for treatment of hepatocarcinomas. 相似文献
14.
Douty B Wayland B Ala PJ Bower MJ Pruitt J Bostrom L Wei M Klabe R Gonneville L Wynn R Burn TC Liu PC Combs AP Yue EW 《Bioorganic & medicinal chemistry letters》2008,18(1):66-71
The structure-based design and synthesis of isothiazolidinone (IZD) inhibitors of PTP1B containing imidazoles and imidazolines and their modification to interact with the B site of PTP1B are described here. The X-ray crystal structures of 3I and 4I complexed with PTP1B were solved and revealed the inhibitors are interacting extensively with the B site of the enzyme. 相似文献
15.
Protein-tyrosine phosphatase 1B as new activator for hepatic lipogenesis via sterol regulatory element-binding protein-1 gene expression 总被引:7,自引:0,他引:7
Shimizu S Ugi S Maegawa H Egawa K Nishio Y Yoshizaki T Shi K Nagai Y Morino K Nemoto K Nakamura T Bryer-Ash M Kashiwagi A 《The Journal of biological chemistry》2003,278(44):43095-43101
16.
PTP1B modulates the association of beta-catenin with N-cadherin through binding to an adjacent and partially overlapping target site 总被引:5,自引:0,他引:5
The nonreceptor tyrosine phosphatase PTP1B associates with the cytoplasmic domain of N-cadherin and may regulate cadherin function through dephosphorylation of beta-catenin. We have now identified the domain on N-cadherin to which PTP1B binds and characterized the effect of perturbing this domain on cadherin function. Deletion constructs lacking amino acids 872-891 fail to bind PTP1B. This domain partially overlaps with the beta-catenin binding domain. To further define the relationship of these two sites, we used peptides to compete in vitro binding. A peptide representing the most NH(2)-terminal 8 amino acids of the PTP1B binding site, the region of overlap with the beta-catenin target, effectively competes for binding of beta-catenin but is much less effective in competing PTP1B, whereas two peptides representing the remaining 12 amino acids have no effect on beta-catenin binding but effectively compete for PTP1B binding. Introduction into embryonic chick retina cells of a cell-permeable peptide mimicking the 8 most COOH-terminal amino acids in the PTP1B target domain, the region most distant from the beta-catenin target site, prevents binding of PTP1B, increases the pool of free, tyrosine-phosphorylated beta-catenin, and results in loss of N-cadherin function. N-cadherin lacking this same region of the PTP1B target site does not associate with PTP1B or beta-catenin and is not efficiently expressed at the cell surface of transfected L cells. Thus, interaction of PTP1B with N-cadherin is essential for its association with beta-catenin, stable expression at the cell surface, and consequently, cadherin function. 相似文献
17.
Liu DG Gao Y Voigt JH Lee K Nicklaus MC Wu L Zhang ZY Burke TR 《Bioorganic & medicinal chemistry letters》2003,13(18):3005-3007
Previously, it had been reported that 6-(phosphonodifluoromethyl)-2-naphthoic acid binds to the protein-tyrosine phosphatase PTP1B with its 2-carboxyl group interacting only indirectly through a bridging water molecule. Reported herein is a family of new analogues that utilize acylsulfonamido functionality both to mimic this water of hydration and to provide an additional new site for elaboration not found in the parent carboxyl-containing analogue. Target acylsulfonamides were prepared in two steps from commercially available primary sulfonamides, which were selected based on in silico screening for their potential ability to interact with one of three binding surfaces proximal to the PTP1B catalytic site. In general, modest potency enhancements were observed. Arylacylsulfonamides represent a structure-based extension of inhibitor design that may have broader utility in the development of PTP1B inhibitors. 相似文献
18.
Scapin G Patel SB Becker JW Wang Q Desponts C Waddleton D Skorey K Cromlish W Bayly C Therien M Gauthier JY Li CS Lau CK Ramachandran C Kennedy BP Asante-Appiah E 《Biochemistry》2003,42(39):11451-11459
Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the regulation of the insulin signaling pathway and represents an attractive target for the design of inhibitors in the treatment of type 2 diabetes and obesity. Inspection of the structure of PTP1B indicates that potent PTP1B inhibitors may be obtained by targeting a secondary aryl phosphate-binding site as well as the catalytic site. We report here the crystal structures of PTP1B in complex with first and second generation aryldifluoromethyl-phosphonic acid inhibitors. While all compounds bind in a previously unexploited binding pocket near the primary binding site, the second generation compounds also reach into the secondary binding site, and exhibit moderate selectivity for PTP1B over the closely related T-cell phosphatase. The molecular basis for the selectivity has been confirmed by single point mutation at position 52, where the two phosphatases differ by a phenylalanine-to-tyrosine switch. These compounds present a novel platform for the development of potent and selective PTP1B inhibitors. 相似文献
19.
Kim S Na M Oh H Jang J Sohn CB Kim BY Oh WK Ahn JS 《Journal of enzyme inhibition and medicinal chemistry》2006,21(4):379-383
Protein tyrosine phosphatase 1B (PTP1B) is considered as a therapeutic target for the treatment of diabetes and obesity. In our preliminary screening study, a MeOH extract of the aerial part of Siegesbeckia glabrescens was found to inhibit PTP1B activity at 30 microg/mL. Bioassay-guided fractionation led to the isolation of two active diterpenes, ent-16betaH, 17-isobutyryloxy-kauran-19-oic acid (1) and ent-16betaH, 17-acetoxy-18-isobutyryloxy-kauran-19-oic acid (2), along with ent- 16betaH, 17-hydroxykauran-19-oic acid (3). Compounds 1 and 2 inhibited the PTP1B activity with IC50 values of 8.7 +/- 0.9 and 30.6 +/- 2.1 microM, respectively. Kinetic studies suggest that both 1 and 2 are non-competitive inhibitors of PTP1B. However, compound 3 substituted with a hydroxyl group at C-17 in kaurane-type showed no inhibitory effects towards PTP1B. 相似文献
20.
Crystal structure of PTP1B complexed with a potent and selective bidentate inhibitor 总被引:4,自引:0,他引:4
Sun JP Fedorov AA Lee SY Guo XL Shen K Lawrence DS Almo SC Zhang ZY 《The Journal of biological chemistry》2003,278(14):12406-12414
Protein-tyrosine phosphatase 1B (PTP1B) has been implicated as an important regulator in several signaling pathways including those initiated by insulin and leptin. Potent and specific PTP1B inhibitors could serve as useful tools in elucidating the physiological functions of PTP1B and may constitute valuable therapeutics in the treatment of several human diseases. We have determined the crystal structure of PTP1B in complex with compound 2, the most potent and selective PTP1B inhibitor reported to date. The structure at 2.15-A resolution reveals that compound 2 simultaneously binds to the active site and a unique proximal noncatalytic site formed by Lys-41, Arg-47, and Asp-48. The structural data are further corroborated by results from kinetic analyses of the interactions of PTP1B and its site-directed mutants with compound 2 and several of its variants. Although many of the residues important for interactions between PTP1B and compound 2 are not unique to PTP1B, the combinations of all contact residues differ between PTP isozymes, which provide a structural basis for potent and selective PTP1B inhibition. Our data further suggest that potent, yet highly selective, PTP1B inhibitory agents can be acquired by targeting the area defined by residues Lys-41, Arg-47, and Asp-48, in addition to the previously identified second aryl phosphate-binding pocket. 相似文献