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Structural basis of serine/threonine phosphatase inhibition by the archetypal small molecules cantharidin and norcantharidin.

Bertini I, Calderone V, Fragai M, Luchinat C, Talluri E
J Med Chem 52 4838-43 (2009)
Related entries: 3h60, 3h61, 3h63, 3h64, 3h66, 3h67, 3h68, 3h69

Cited: 38 times
EuropePMC logo PMID: 19601647

Abstract

The inhibition of a subgroup of human serine/threonine protein phosphatases is responsible for the cytotoxicity of cantharidin and norcantharidin against tumor cells. It is shown that the anhydride rings of cantharidin and norcantharidin are hydrolyzed when bound to the catalytic domain of the human serine/threonine protein phosphatases 5 (PP5c), and the high-resolution crystal structures of PP5c complexed with the corresponding dicarboxylic acid derivatives of the two molecules are reported. Norcantharidin shows a unique binding conformation with the catalytically active Mn2PP5c, while cantharidin is characterized by a double conformation in its binding mode to the protein. Different binding modes of norcantharidin are observed depending of whether the starting ligand is in the anhydride or in the dicarboxylic acid form. All these structures will provide the basis for the rational design of new cantharidin-based drugs.

Reviews - 3h62 mentioned but not cited (1)

  1. Viewing serine/threonine protein phosphatases through the eyes of drug designers. Zhang M, Yogesha SD, Mayfield JE, Gill GN, Zhang Y. FEBS J 280 4739-4760 (2013)

Articles - 3h62 mentioned but not cited (1)

  1. Deprotonation states of the two active site water molecules regulate the binding of protein phosphatase 5 with its substrate: A molecular dynamics study. Wang L, Yan F. Protein Sci 26 2010-2020 (2017)


Reviews citing this publication (6)

  1. Terpenoids: natural products for cancer therapy. Huang M, Lu JJ, Huang MQ, Bao JL, Chen XP, Wang YT. Expert Opin Investig Drugs 21 1801-1818 (2012)
  2. Cantharidin-based small molecules as potential therapeutic agents. Puerto Galvis CE, Vargas Méndez LY, Kouznetsov VV. Chem Biol Drug Des 82 477-499 (2013)
  3. The phosphoprotein phosphatase family of Ser/Thr phosphatases as principal targets of naturally occurring toxins. Pereira SR, Vasconcelos VM, Antunes A. Crit Rev Toxicol 41 83-110 (2011)
  4. Inhibitors of Serine/Threonine Protein Phosphatases: Biochemical and Structural Studies Provide Insight for Further Development. Swingle MR, Honkanen RE. Curr Med Chem 26 2634-2660 (2019)
  5. Norcantharidin analogues: a patent review (2006 - 2010). Deng L, Tang S. Expert Opin Ther Pat 21 1743-1753 (2011)
  6. Antitumor potential of the protein phosphatase inhibitor, cantharidin, and selected derivatives. Ren Y, Kinghorn AD. Bioorg Med Chem 32 116012 (2021)

Articles citing this publication (30)

  1. Folate receptor-targeted liposomes loaded with a diacid metabolite of norcantharidin enhance antitumor potency for H22 hepatocellular carcinoma both in vitro and in vivo. Liu MC, Liu L, Wang XR, Shuai WP, Hu Y, Han M, Gao JQ. Int J Nanomedicine 11 1395-1412 (2016)
  2. Exploration of new drug-like inhibitors for serine/threonine protein phosphatase 5 of Plasmodium falciparum: a docking and simulation study. Gupta S, Jadaun A, Kumar H, Raj U, Varadwaj PK, Rao AR. J Biomol Struct Dyn 33 2421-2441 (2015)
  3. Synthesis and biological activity of Delta-5,6-norcantharimides: importance of the 5,6-bridge. Thaqi A, Scott JL, Gilbert J, Sakoff JA, McCluskey A. Eur J Med Chem 45 1717-1723 (2010)
  4. Transcriptional responses to cantharidin, a protein phosphatase inhibitor, in Arabidopsis thaliana reveal the involvement of multiple signal transduction pathways. Bajsa J, Pan Z, Duke SO. Physiol Plant 143 188-205 (2011)
  5. Crystal structures and mutagenesis of PPP-family ser/thr protein phosphatases elucidate the selectivity of cantharidin and novel norcantharidin-based inhibitors of PP5C. Chattopadhyay D, Swingle MR, Salter EA, Wood E, D'Arcy B, Zivanov C, Abney K, Musiyenko A, Rusin SF, Kettenbach A, Yet L, Schroeder CE, Golden JE, Dunham WH, Gingras AC, Banerjee S, Forbes D, Wierzbicki A, Honkanen RE. Biochem Pharmacol 109 14-26 (2016)
  6. Insights into the key interactions between human protein phosphatase 5 and cantharidin using molecular dynamics and site-directed mutagenesis bioassays. Liu JY, Chen XE, Zhang YL. Sci Rep 5 12359 (2015)
  7. Structure-Activity Relationship Studies Using Natural and Synthetic Okadaic Acid/Dinophysistoxin Toxins. Twiner MJ, Doucette GJ, Pang Y, Fang C, Forsyth CJ, Miles CO. Mar Drugs 14 E207 (2016)
  8. Cantharidin impedes the activity of protein serine/threonine phosphatase in Plutella xylostella. Chen X, Liu J, Zhang Y. Mol Biosyst 10 240-250 (2014)
  9. Non-target effects on soil microbial parameters of the synthetic pesticide carbendazim with the biopesticides cantharidin and norcantharidin. Shao H, Zhang Y. Sci Rep 7 5521 (2017)
  10. Norcantharidin attenuates tubulointerstitial fibrosis in rat models with diabetic nephropathy. Li Y, Chen Q, Liu FY, Peng YM, Hou T, Duan SB, Li J, Luo JH, Sun L, Ling GH. Ren Fail 33 233-241 (2011)
  11. Cantharidin and its anhydride-modified derivatives: relation of structure to insecticidal activity. Sun W, Liu Z, Zhang Y. Int J Mol Sci 14 1-16 (2012)
  12. Plasmodium berghei serine/threonine protein phosphatase PP5 plays a critical role in male gamete fertility. Zhu X, Sun L, He Y, Wei H, Hong M, Liu F, Liu Q, Cao Y, Cui L. Int J Parasitol 49 685-695 (2019)
  13. Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway. Li Y, Chen Q, Liu FY, Peng YM, Wang S, Li J, Li J, Duan SB, Sun L, Ling GH, Luo JH. Lab Invest 91 1706-1716 (2011)
  14. Synthesis and biological evaluation of norcantharidin derivatives as protein phosphatase-1 inhibitors. Zhao J, Guan XW, Chen SW, Hui L. Bioorg Med Chem Lett 25 363-366 (2015)
  15. Formulation and evaluation of norcanthridin nanoemulsions against the Plutella xylostella (Lepidotera: Plutellidae). Zeng L, Liu Y, Pan J, Liu X. BMC Biotechnol 19 16 (2019)
  16. Separation and identification of norcantharidin metabolites in vivo by GC-MS method. Wei C, Teng Y, Wang B, Zhang X, Yuan G, Liu X, Li R, Guo R. J Chromatogr B Analyt Technol Biomed Life Sci 879 1741-1747 (2011)
  17. Cantharidin inhibits competitively heme-Fe(III) binding to the FA1 site of human serum albumin. Polticelli F, Leboffe L, Tortosa V, Trezza V, Fanali G, Fasano M, Ascenzi P. J Mol Recognit 30 (2017)
  18. Determination and pharmacokinetic study of the diacid metabolite of norcantharidin in beagle plasma by use of liquid chromatography-tandem mass spectrometry. Liu M, Ma X, Jin Z, Li W, Guo M, Li F. Anal Bioanal Chem 405 9273-9283 (2013)
  19. Synthesis of optically pure norcantharidin analogue NCA-01, a highly selective protein phosphatase 2B inhibitor, and its derivatives. Shimizu T, Iizuka M, Matsukura H, Hashizume D, Sodeoka M. Chem Asian J 7 1221-1230 (2012)
  20. An Ultra-High-Throughput Screen for Catalytic Inhibitors of Serine/Threonine Protein Phosphatases Types 1 and 5 (PP1C and PP5C). Swingle M, Volmar CH, Saldanha SA, Chase P, Eberhart C, Salter EA, D'Arcy B, Schroeder CE, Golden JE, Wierzbicki A, Hodder P, Honkanen RE. SLAS Discov 22 21-31 (2017)
  21. An unexpected formation of the novel 7-oxa-2-azabicyclo[2.2.1]hept-5-ene skeleton during the reaction of furfurylamine with maleimides and their bioprospection using a zebrafish embryo model. Puerto Galvis CE, Kouznetsov VV. Org Biomol Chem 11 407-411 (2013)
  22. Modeling the antiferromagnetic MnIIMnII system within the protein phosphatase-5 catalytic site. Salter EA, Honkanen RE, Wierzbicki A. J Mol Model 21 14 (2015)
  23. Synthesis and Biological Evaluation of Norcantharidin Derivatives Possessing an Aromatic Amine Moiety as Antifungal Agents. Wang Y, Sun W, Zha S, Wang H, Zhang Y. Molecules 20 21464-21480 (2015)
  24. Molecular cloning and characterization of the calcineurin subunit A from Plutella xylostella. Chen X, Zhang Y. Int J Mol Sci 14 20692-20703 (2013)
  25. Quantum-based modeling implies that bidentate Arg89-substrate binding enhances serine/threonine protein phosphatase-2A(PPP2R5D/PPP2R1A/PPP2CA)-mediated dephosphorylation. Salter EA, Wierzbicki A, Honkanen RE, Swingle MR. Front Cell Dev Biol 11 1141804 (2023)
  26. The Inhibition of Serine/Threonine Protein Phosphatase Type 5 Mediates Cantharidin Toxicity to Control Periplaneta americana (L.). Sun H, Li Y, Li X, Zhang Y. Insects 11 E682 (2020)
  27. Cantharidin induces apoptosis of human triple negative breast cancer cells through mir-607-mediated downregulation of EGFR. Yang T, Yu R, Cheng C, Huo J, Gong Z, Cao H, Hu Y, Dai B, Zhang Y. J Transl Med 21 597 (2023)
  28. Catalytic inhibitor of Protein Phosphatase 5 activates the extrinsic apoptotic pathway by disrupting complex II in kidney cancer. Ahanin EF, Sager RA, Backe SJ, Dunn DM, Dushukyan N, Blanden AR, Mate NA, Suzuki T, Anderson T, Roy M, Oberoi J, Prodromou C, Nsouli I, Daneshvar M, Bratslavsky G, Woodford MR, Bourboulia D, Chisholm JD, Mollapour M. Cell Chem Biol 30 1223-1234.e12 (2023)
  29. Interactions of cantharidin-like inhibitors with human protein phosphatase-5 in a Mg2+ system: molecular dynamics and quantum calculations. Assis LC, de Castro AA, Prandi IG, Mancini DT, de Giacoppo JOS, Savedra RML, de Assis TM, Carregal JB, da Cunha EFF, Ramalho TC. J Mol Model 24 303 (2018)
  30. Tyr306 near the C-terminus of protein phosphatase-1 affects enzyme stability and inhibitor binding. Wang BJ, Tang W, Zhang P, Wei Q. IUBMB Life 63 574-581 (2011)


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