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Crystal structures and inhibitor identification for PTPN5, PTPRR and PTPN7: a family of human MAPK-specific protein tyrosine phosphatases.

Eswaran J, von Kries JP, Marsden B, Longman E, Debreczeni JE, Ugochukwu E, Turnbull A, Lee WH, Knapp S, Barr AJ
Biochem J 395 483-91 (2006)
Related entries: 2bij, 2bv5

Cited: 46 times
EuropePMC logo PMID: 16441242

Abstract

Protein tyrosine phosphatases PTPN5, PTPRR and PTPN7 comprise a family of phosphatases that specifically inactivate MAPKs (mitogen-activated protein kinases). We have determined high-resolution structures of all of the human family members, screened them against a library of 24000 compounds and identified two classes of inhibitors, cyclopenta[c]quinolinecarboxylic acids and 2,5-dimethylpyrrolyl benzoic acids. Comparative structural analysis revealed significant differences within this conserved family that could be explored for the design of selective inhibitors. PTPN5 crystallized, in two distinct crystal forms, with a sulphate ion in close proximity to the active site and the WPD (Trp-Pro-Asp) loop in a unique conformation, not seen in other PTPs, ending in a 3(10)-helix. In the PTPN7 structure, the WPD loop was in the closed conformation and part of the KIM (kinase-interaction motif) was visible, which forms an N-terminal aliphatic helix with the phosphorylation site Thr66 in an accessible position. The WPD loop of PTPRR was open; however, in contrast with the structure of its mouse homologue, PTPSL, a salt bridge between the conserved lysine and aspartate residues, which has been postulated to confer a more rigid loop structure, thereby modulating activity in PTPSL, does not form in PTPRR. One of the identified inhibitor scaffolds, cyclopenta[c]quinoline, was docked successfully into PTPRR, suggesting several possibilities for hit expansion. The determined structures together with the established SAR (structure-activity relationship) propose new avenues for the development of selective inhibitors that may have therapeutic potential for treating neurodegenerative diseases in the case of PTPRR or acute myeloblastic leukaemia targeting PTPN7.

Articles - 2a8b mentioned but not cited (6)

  1. Large-scale structural analysis of the classical human protein tyrosine phosphatome. Barr AJ, Ugochukwu E, Lee WH, King ON, Filippakopoulos P, Alfano I, Savitsky P, Burgess-Brown NA, Müller S, Knapp S. Cell 136 352-363 (2009)
  2. Crystal structures and inhibitor identification for PTPN5, PTPRR and PTPN7: a family of human MAPK-specific protein tyrosine phosphatases. Eswaran J, von Kries JP, Marsden B, Longman E, Debreczeni JE, Ugochukwu E, Turnbull A, Lee WH, Knapp S, Barr AJ. Biochem J 395 483-491 (2006)
  3. Visualizing active-site dynamics in single crystals of HePTP: opening of the WPD loop involves coordinated movement of the E loop. Critton DA, Tautz L, Page R. J Mol Biol 405 619-629 (2011)
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  5. Chemical activation of divergent protein tyrosine phosphatase domains with cyanine-based biarsenicals. Plaman BA, Chan WC, Bishop AC. Sci Rep 9 16148 (2019)
  6. Integration of Adenylate Kinase 1 with Its Peptide Conformational Imprint. Wu CH, Lin CY, Lin TC, Tai DF. Int J Mol Sci 23 6521 (2022)


Reviews citing this publication (12)

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Articles citing this publication (28)

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  2. Brain somatic mutations observed in Alzheimer's disease associated with aging and dysregulation of tau phosphorylation. Park JS, Lee J, Jung ES, Kim MH, Kim IB, Son H, Kim S, Kim S, Park YM, Mook-Jung I, Yu SJ, Lee JH. Nat Commun 10 3090 (2019)
  3. Gene expression profiling of post-mortem orbitofrontal cortex in violent suicide victims. Thalmeier A, Dickmann M, Giegling I, Schneider B, M Hartmann A, Maurer K, Schnabel A, Kauert G, Möller HJ, Rujescu D. Int J Neuropsychopharmacol 11 217-228 (2008)
  4. MAPK-specific tyrosine phosphatases: new targets for drug discovery? Barr AJ, Knapp S. Trends Pharmacol Sci 27 525-530 (2006)
  5. Development and implementation of a 384-well homogeneous fluorescence intensity high-throughput screening assay to identify mitogen-activated protein kinase phosphatase-1 dual-specificity protein phosphatase inhibitors. Johnston PA, Foster CA, Shun TY, Skoko JJ, Shinde S, Wipf P, Lazo JS. Assay Drug Dev Technol 5 319-332 (2007)
  6. Molecular mechanism of ERK dephosphorylation by striatal-enriched protein tyrosine phosphatase. Li R, Xie DD, Dong JH, Li H, Li KS, Su J, Chen LZ, Xu YF, Wang HM, Gong Z, Cui GY, Yu X, Wang K, Yao W, Xin T, Li MY, Xiao KH, An XF, Huo Y, Xu ZG, Sun JP, Pang Q. J Neurochem 128 315-329 (2014)
  7. Structural basis of substrate recognition by hematopoietic tyrosine phosphatase. Critton DA, Tortajada A, Stetson G, Peti W, Page R. Biochemistry 47 13336-13345 (2008)
  8. Cdc25B dual-specificity phosphatase inhibitors identified in a high-throughput screen of the NIH compound library. Johnston PA, Foster CA, Tierno MB, Shun TY, Shinde SN, Paquette WD, Brummond KM, Wipf P, Lazo JS. Assay Drug Dev Technol 7 250-265 (2009)
  9. The protein tyrosine phosphatase receptor type R gene is an early and frequent target of silencing in human colorectal tumorigenesis. Menigatti M, Cattaneo E, Sabates-Bellver J, Ilinsky VV, Went P, Buffoli F, Marquez VE, Jiricny J, Marra G. Mol Cancer 8 124 (2009)
  10. Inhibition of hematopoietic protein tyrosine phosphatase augments and prolongs ERK1/2 and p38 activation. Sergienko E, Xu J, Liu WH, Dahl R, Critton DA, Su Y, Brown BT, Chan X, Yang L, Bobkova EV, Vasile S, Yuan H, Rascon J, Colayco S, Sidique S, Cosford ND, Chung TD, Mustelin T, Page R, Lombroso PJ, Tautz L. ACS Chem Biol 7 367-377 (2012)
  11. Reduced body weight in male Tspan8-deficient mice. Champy MF, Le Voci L, Selloum M, Peterson LB, Cumiskey AM, Blom D. Int J Obes (Lond) 35 605-617 (2011)
  12. The differential regulation of p38α by the neuronal kinase interaction motif protein tyrosine phosphatases, a detailed molecular study. Francis DM, Kumar GS, Koveal D, Tortajada A, Page R, Peti W. Structure 21 1612-1623 (2013)
  13. Interface analysis of the complex between ERK2 and PTP-SL. Balasu MC, Spiridon LN, Miron S, Craescu CT, Scheidig AJ, Petrescu AJ, Szedlacsek SE. PLoS One 4 e5432 (2009)
  14. Small molecule receptor protein tyrosine phosphatase γ (RPTPγ) ligands that inhibit phosphatase activity via perturbation of the tryptophan-proline-aspartate (WPD) loop. Sheriff S, Beno BR, Zhai W, Kostich WA, McDonnell PA, Kish K, Goldfarb V, Gao M, Kiefer SE, Yanchunas J, Huang Y, Shi S, Zhu S, Dzierba C, Bronson J, Macor JE, Appiah KK, Westphal RS, O'Connell J, Gerritz SW. J Med Chem 54 6548-6562 (2011)
  15. An iminocoumarin-based fluorescent probe for the selective detection of dual-specific protein tyrosine phosphatases. Kim TI, Jeong MS, Chung SJ, Kim Y. Chemistry 16 5297-5300 (2010)
  16. Functional assignment of MAPK phosphatase domains. Nordle AK, Rios P, Gaulton A, Pulido R, Attwood TK, Tabernero L. Proteins 69 19-31 (2007)
  17. Sequence-specific 1H, 13C and 15N backbone resonance assignments of the 34 kDa catalytic domain of human PTPN7. Jeeves M, McClelland DM, Barr AJ, Overduin M. Biomol NMR Assign 2 101-103 (2008)
  18. X-ray Characterization and Structure-Based Optimization of Striatal-Enriched Protein Tyrosine Phosphatase Inhibitors. Witten MR, Wissler L, Snow M, Geschwindner S, Read JA, Brandon NJ, Nairn AC, Lombroso PJ, Käck H, Ellman JA. J Med Chem 60 9299-9319 (2017)
  19. Missense Variant in MAPK Inactivator PTPN5 Is Associated with Decreased Severity of Post-Burn Hypertrophic Scarring. Sood RF, Arbabi S, Honari S, Gibran NS. PLoS One 11 e0149206 (2016)
  20. Association of Extracellular Signal-Regulated Kinase Genes With Myopia: A Longitudinal Study of Chinese Children. Xiao H, Lin S, Jiang D, Lin Y, Liu L, Zhang Q, He J, Chen Y. Front Genet 12 654869 (2021)
  21. Effects of protonation state of Asp181 and position of active site water molecules on the conformation of PTP1B. Ozcan A, Olmez EO, Alakent B. Proteins 81 788-804 (2013)
  22. A structural comparative approach to identifying novel antimalarial inhibitors. Franco J, Blackie MA, Toth D, Smith PJ, Capuano J, Fastnacht K, Berkes C. Comput Biol Chem 45 42-47 (2013)
  23. Inhibition of striatal-enriched protein tyrosine phosphatase by targeting computationally revealed cryptic pockets. Hou X, Sun JP, Ge L, Liang X, Li K, Zhang Y, Fang H. Eur J Med Chem 190 112131 (2020)
  24. Sequence-specific backbone ¹H, ¹³C and ¹⁵N assignments of the 34 kDa catalytic domain of PTPN5 (STEP). Francis DM, Page R, Peti W. Biomol NMR Assign 8 185-188 (2014)
  25. A New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis. Adams J, Thornton BP, Tabernero L. Int J Mol Sci 22 12206 (2021)
  26. Extracellular vesicles microRNA-592 of melanoma stem cells promotes metastasis through activation of MAPK/ERK signaling pathway by targeting PTPN7 in non-stemness melanoma cells. Zhang Y, Chen Y, Shi L, Li J, Wan W, Li B, Liu D, Li X, Chen Y, Xiang M, Chen H, Zeng B, Xing HR, Wang J. Cell Death Discov 8 428 (2022)
  27. Pan-cancer analysis revealing that PTPN2 is an indicator of risk stratification for acute myeloid leukemia. Wang X, Wu S, Sun L, Jin P, Zhang J, Liu W, Zhan Z, Wang Z, Liu X, He L. Sci Rep 13 18372 (2023)
  28. Pushed to extremes: distinct effects of high temperature versus pressure on the structure of STEP. Guerrero L, Ebrahim A, Riley BT, Kim M, Huang Q, Finke AD, Keedy DA. Commun Biol 7 59 (2024)


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