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Structural basis for the allosteric regulation and substrate recognition of human cytosolic 5'-nucleotidase II.

Walldén K, Nordlund P
J Mol Biol 408 684-96 (2011)
Related entries: 2xcv, 2xcw, 2xcx, 2xjb, 2xjc, 2xjd, 2xje

Cited: 31 times
EuropePMC logo PMID: 21396942

Abstract

Cytosolic 5'-nucleotidase II (cN-II) catalyzes the dephosphorylation of 6-hydroxypurine nucleoside 5'-monophosphates and participates in the regulation of purine nucleotide pools within the cell. It interferes with the phosphorylation-dependent activation of nucleoside analogues used in the treatment of cancer and viral diseases. It is allosterically activated by a number of phosphate-containing cellular metabolites such as ATP, diadenosine polyphosphates, and 2,3-bisphosphoglycerate, which couple its activity with the metabolic state of the cell. We present seven high-resolution structures of human cN-II, including a ligand-free form and complexes with various substrates and effectors. These structures reveal the structural basis for the allosteric activation of cN-II, uncovering a mechanism where an effector-induced disorder-to-order transition generates rearrangements within the catalytic site and the subsequent coordination of the catalytically essential magnesium. Central to the activation is the large transition of the catalytically essential Asp356. This study also provides the structural basis for the substrate specificity of cN-II, where Arg202, Asp206, and Phe157 seem to be important residues for purine/pyrimidine selectivity. These structures provide a comprehensive structural basis for the design of cN-II inhibitors. They also contribute to the understanding of how the nucleotide salvage pathway is regulated at a molecular level.

Reviews citing this publication (9)

  1. Enzyme promiscuity: engine of evolutionary innovation. Pandya C, Farelli JD, Dunaway-Mariano D, Allen KN. J Biol Chem 289 30229-30236 (2014)
  2. SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity. Mauney CH, Hollis T. Autoimmunity 51 96-110 (2018)
  3. Emerging Role of Purine Metabolizing Enzymes in Brain Function and Tumors. Garcia-Gil M, Camici M, Allegrini S, Pesi R, Petrotto E, Tozzi MG. Int J Mol Sci 19 E3598 (2018)
  4. Interplay between adenylate metabolizing enzymes and AMP-activated protein kinase. Camici M, Allegrini S, Tozzi MG. FEBS J 285 3337-3352 (2018)
  5. Genetics and mechanisms of NT5C2-driven chemotherapy resistance in relapsed ALL. Dieck CL, Ferrando A. Blood 133 2263-2268 (2019)
  6. Metabolic Aspects of Adenosine Functions in the Brain. Garcia-Gil M, Camici M, Allegrini S, Pesi R, Tozzi MG. Front Pharmacol 12 672182 (2021)
  7. Promiscuity in the Enzymatic Catalysis of Phosphate and Sulfate Transfer. Pabis A, Duarte F, Kamerlin SC. Biochemistry 55 3061-3081 (2016)
  8. The druggability of intracellular nucleotide-degrading enzymes. Rampazzo C, Tozzi MG, Dumontet C, Jordheim LP. Cancer Chemother Pharmacol 77 883-893 (2016)
  9. The mysterious diadenosine tetraphosphate (AP4A). Zegarra V, Mais CN, Freitag J, Bange G. Microlife 4 uqad016 (2023)

Articles citing this publication (22)

  1. The structural basis of ATP as an allosteric modulator. Lu S, Huang W, Wang Q, Shen Q, Li S, Nussinov R, Zhang J. PLoS Comput Biol 10 e1003831 (2014)
  2. Structure and Mechanisms of NT5C2 Mutations Driving Thiopurine Resistance in Relapsed Lymphoblastic Leukemia. Dieck CL, Tzoneva G, Forouhar F, Carpenter Z, Ambesi-Impiombato A, Sánchez-Martín M, Kirschner-Schwabe R, Lew S, Seetharaman J, Tong L, Ferrando AA. Cancer Cell 34 136-147.e6 (2018)
  3. NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap4A) and Down-Regulates Immune Response and Cancer Promotion Genes. Marriott AS, Vasieva O, Fang Y, Copeland NA, McLennan AG, Jones NJ. PLoS One 11 e0154674 (2016)
  4. Relapsed acute lymphoblastic leukemia-specific mutations in NT5C2 cluster into hotspots driving intersubunit stimulation. Hnízda A, Fábry M, Moriyama T, Pachl P, Kugler M, Brinsa V, Ascher DB, Carroll WL, Novák P, Žaliová M, Trka J, Řezáčová P, Yang JJ, Veverka V. Leukemia 32 1393-1403 (2018)
  5. Evolutionary and structural analyses of mammalian haloacid dehalogenase-type phosphatases AUM and chronophin provide insight into the basis of their different substrate specificities. Seifried A, Knobloch G, Duraphe PS, Segerer G, Manhard J, Schindelin H, Schultz J, Gohla A. J Biol Chem 289 3416-3431 (2014)
  6. Cell proliferation and drug sensitivity of human glioblastoma cells are altered by the stable modulation of cytosolic 5'-nucleotidase II. Cividini F, Cros-Perrial E, Pesi R, Machon C, Allegrini S, Camici M, Dumontet C, Jordheim LP, Tozzi MG. Int J Biochem Cell Biol 65 222-229 (2015)
  7. Structural insights into the inhibition of cytosolic 5'-nucleotidase II (cN-II) by ribonucleoside 5'-monophosphate analogues. Gallier F, Lallemand P, Meurillon M, Jordheim LP, Dumontet C, Périgaud C, Lionne C, Peyrottes S, Chaloin L. PLoS Comput Biol 7 e1002295 (2011)
  8. Identification of allosteric inhibitors of the ecto-5'-nucleotidase (CD73) targeting the dimer interface. Rahimova R, Fontanel S, Lionne C, Jordheim LP, Peyrottes S, Chaloin L. PLoS Comput Biol 14 e1005943 (2018)
  9. Allosteric regulation and substrate activation in cytosolic nucleotidase II from Legionella pneumophila. Srinivasan B, Forouhar F, Shukla A, Sampangi C, Kulkarni S, Abashidze M, Seetharaman J, Lew S, Mao L, Acton TB, Xiao R, Everett JK, Montelione GT, Tong L, Balaram H. FEBS J 281 1613-1628 (2014)
  10. Crystal structures of the novel cytosolic 5'-nucleotidase IIIB explain its preference for m7GMP. Monecke T, Buschmann J, Neumann P, Wahle E, Ficner R. PLoS One 9 e90915 (2014)
  11. Cytosolic 5'-Nucleotidase II Silencing in a Human Lung Carcinoma Cell Line Opposes Cancer Phenotype with a Concomitant Increase in p53 Phosphorylation. Pesi R, Petrotto E, Colombaioni L, Allegrini S, Garcia-Gil M, Camici M, Jordheim LP, Tozzi MG. Int J Mol Sci 19 E2115 (2018)
  12. Structure-activity relationships of β-hydroxyphosphonate nucleoside analogues as cytosolic 5'-nucleotidase II potential inhibitors: synthesis, in vitro evaluation and molecular modeling studies. Meurillon M, Marton Z, Hospital A, Jordheim LP, Béjaud J, Lionne C, Dumontet C, Périgaud C, Chaloin L, Peyrottes S. Eur J Med Chem 77 18-37 (2014)
  13. The purine analog fludarabine acts as a cytosolic 5'-nucleotidase II inhibitor. Cividini F, Pesi R, Chaloin L, Allegrini S, Camici M, Cros-Perrial E, Dumontet C, Jordheim LP, Tozzi MG. Biochem Pharmacol 94 63-68 (2015)
  14. Oligomeric interface modulation causes misregulation of purine 5´-nucleotidase in relapsed leukemia. Hnízda A, Škerlová J, Fábry M, Pachl P, Šinalová M, Vrzal L, Man P, Novák P, Řezáčová P, Veverka V. BMC Biol 14 91 (2016)
  15. Evidence for a Cross-Talk Between Cytosolic 5'-Nucleotidases and AMP-Activated Protein Kinase. Camici M, Garcia-Gil M, Allegrini S, Pesi R, Tozzi MG. Front Pharmacol 11 609849 (2020)
  16. The rs11191580 variant of the NT5C2 gene is associated with schizophrenia and symptom severity in a South Chinese Han population: evidence from GWAS. Li Z, Jiang J, Long J, Ling W, Huang G, Guo X, Su L. Braz J Psychiatry 39 104-109 (2017)
  17. Cytosolic 5'-Nucleotidase II Is a Sensor of Energy Charge and Oxidative Stress: A Possible Function as Metabolic Regulator. Pesi R, Allegrini S, Balestri F, Garcia-Gil M, Cividini F, Colombaioni L, Jordheim LP, Camici M, Tozzi MG. Cells 10 182 (2021)
  18. Structural basis of substrate specificity and selectivity of murine cytosolic 5'-nucleotidase III. Grobosky CL, Lopez JB, Rennie S, Skopelitis DJ, Wiest AT, Bingman CA, Bitto E. J Mol Biol 423 540-554 (2012)
  19. A native electrophoretic technique to study oligomerization and activity of cytosolic 5′-nucleotidase II. Filoni DN, Pesi R, Allegrini S, Camici M, Tozzi MG. Anal Bioanal Chem 405 8951-8954 (2013)
  20. Beta-hydroxyphosphonate ribonucleoside analogues derived from 4-substituted-1,2,3-triazoles as IMP/GMP mimics: synthesis and biological evaluation. Nguyen Van T, Hospital A, Lionne C, Jordheim LP, Dumontet C, Périgaud C, Chaloin L, Peyrottes S. Beilstein J Org Chem 12 1476-1486 (2016)
  21. Initial studies to define the physiologic role of cN-II. Filoni DN, Pesi R, Careddu MG, Camici M, Allegrini S, Collavoli A, Scarfone I, Zucchi F, Galli A, Tozzi MG. Nucleosides Nucleotides Nucleic Acids 30 1155-1160 (2011)
  22. Pharmacologic Inhibition of NT5C2 Reverses Genetic and Nongenetic Drivers of 6-MP Resistance in Acute Lymphoblastic Leukemia. Reglero C, Dieck CL, Zask A, Forouhar F, Laurent AP, Lin WW, Albero R, Miller HI, Ma C, Gastier-Foster JM, Loh ML, Tong L, Stockwell BR, Palomero T, Ferrando AA. Cancer Discov 12 2646-2665 (2022)


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