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Crystal structure of human phosphodiesterase 3B: atomic basis for substrate and inhibitor specificity.

Scapin G, Patel SB, Chung C, Varnerin JP, Edmondson SD, Mastracchio A, Parmee ER, Singh SB, Becker JW, Van der Ploeg LH, Tota MR
Biochemistry 43 6091-100 (2004)
Cited: 60 times
EuropePMC logo PMID: 15147193

Abstract

Phosphodiesterases (PDEs) are enzymes that modulate cyclic nucleotide signaling and as such are clinical targets for a range of disorders including congestive heart failure, erectile dysfunction, and inflammation. The PDE3 family comprises two highly homologous subtypes expressed in different tissues, and inhibitors of this family have been shown to increase lipolysis in adipocytes. A specific PDE3B (the lipocyte-localized subtype) inhibitor would be a very useful tool to evaluate the effects of PDE3 inhibition on lipolysis and metabolic rate and might become a novel tool for treatment of obesity. We report here the three-dimensional structures of the catalytic domain of human PDE3B in complex with a generic PDE inhibitor and a novel PDE3 selective inhibitor. These structures explain the dual cAMP/cGMP binding capabilities of PDE3, provide the molecular basis for inhibitor specificity, and can supply a valid platform for the design of improved compounds.

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  16. New Prospective Phosphodiesterase Inhibitors: Phosphorylated Oxazole Derivatives in Treatment of Hypertension. Nizhenkovska IV, Matskevych KV, Golovchenko OI, Golovchenko OV, Kustovska AD, Van M. Adv Pharm Bull 13 399-407 (2023)


Reviews citing this publication (8)

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  5. Structure-Bioactivity Relationships of Methylxanthines: Trying to Make Sense of All the Promises and the Drawbacks. Monteiro JP, Alves MG, Oliveira PF, Silva BM. Molecules 21 E974 (2016)
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  7. Treating COPD with PDE 4 inhibitors. Brown WM. Int J Chron Obstruct Pulmon Dis 2 517-533 (2007)
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Articles citing this publication (35)

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  13. Phosphodiesterase-5 Gln817 is critical for cGMP, vardenafil, or sildenafil affinity: its orientation impacts cGMP but not cAMP affinity. Zoraghi R, Corbin JD, Francis SH. J Biol Chem 281 5553-5558 (2006)
  14. Kinetic properties of Ca2+/calmodulin-dependent phosphodiesterase isoforms dictate intracellular cAMP dynamics in response to elevation of cytosolic Ca2+. Goraya TA, Masada N, Ciruela A, Willoughby D, Clynes MA, Cooper DM. Cell Signal 20 359-374 (2008)
  15. Phosphodiesterase inhibitors. Part 3: Design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-dihydropyridazinones with anti-inflammatory and bronchodilatory activity. Ochiai K, Takita S, Eiraku T, Kojima A, Iwase K, Kishi T, Fukuchi K, Yasue T, Adams DR, Allcock RW, Jiang Z, Kohno Y. Bioorg Med Chem 20 1644-1658 (2012)
  16. Studies on the antiplatelet and antithrombotic profile of anti-inflammatory coumarin derivatives. Kontogiorgis C, Nicolotti O, Mangiatordi GF, Tognolini M, Karalaki F, Giorgio C, Patsilinakos A, Carotti A, Hadjipavlou-Litina D, Barocelli E. J Enzyme Inhib Med Chem 30 925-933 (2015)
  17. Phosphodiesterase inhibitors. Part 1: Synthesis and structure-activity relationships of pyrazolopyridine-pyridazinone PDE inhibitors developed from ibudilast. Allcock RW, Blakli H, Jiang Z, Johnston KA, Morgan KM, Rosair GM, Iwase K, Kohno Y, Adams DR. Bioorg Med Chem Lett 21 3307-3312 (2011)
  18. Phosphodiesterase inhibitors. Part 5: hybrid PDE3/4 inhibitors as dual bronchorelaxant/anti-inflammatory agents for inhaled administration. Ochiai K, Takita S, Kojima A, Eiraku T, Iwase K, Kishi T, Ohinata A, Yageta Y, Yasue T, Adams DR, Kohno Y. Bioorg Med Chem Lett 23 375-381 (2013)
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  21. Design, synthesis and biological evaluation of 6-(benzyloxy)-4-methylquinolin-2(1H)-one derivatives as PDE3 inhibitors. Nikpour M, Sadeghian H, Saberi MR, Nick RS, Seyedi SM, Hosseini A, Parsaee H, Bozorg AT. Bioorg Med Chem 18 855-862 (2010)
  22. Phosphodiesterase inhibitors. Part 4: design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-4,4-dimethylpyrazolones. Ochiai K, Takita S, Kojima A, Eiraku T, Ando N, Iwase K, Kishi T, Ohinata A, Yageta Y, Yasue T, Adams DR, Kohno Y. Bioorg Med Chem Lett 22 5833-5838 (2012)
  23. Determinants for phosphodiesterase 6 inhibition by its gamma-subunit. Zhang Z, Artemyev NO. Biochemistry 49 3862-3867 (2010)
  24. Structure of PDE3A-SLFN12 complex and structure-based design for a potent apoptosis inducer of tumor cells. Chen J, Liu N, Huang Y, Wang Y, Sun Y, Wu Q, Li D, Gao S, Wang HW, Huang N, Qi X, Wang X. Nat Commun 12 6204 (2021)
  25. Synthesis, docking studies, pharmacological activity and toxicity of a novel pyrazole derivative (LQFM 021)--possible effects on phosphodiesterase. Ramos Martins D, Pazini F, de Medeiros Alves V, Santana de Moura S, Morais Lião L, Torquato Quezado de Magalhães M, Campos Valadares M, Horta Andrade C, Menegatti R, Lavorenti Rocha M. Chem Pharm Bull (Tokyo) 61 524-531 (2013)
  26. Enantiomer discrimination illustrated by the high resolution crystal structures of type 4 phosphodiesterase. Huai Q, Sun Y, Wang H, Macdonald D, Aspiotis R, Robinson H, Huang Z, Ke H. J Med Chem 49 1867-1873 (2006)
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  28. Design, synthesis and pharmacological evaluation of 6-hydroxy-4-methylquinolin-2(1H)-one derivatives as inotropic agents. Sadeghian H, Seyedi SM, Saberi MR, Nick RS, Hosseini A, Bakavoli M, Mansouri SM, Parsaee H. J Enzyme Inhib Med Chem 24 918-929 (2009)
  29. Synthesis, in vitro antiplatelet activity and molecular modelling studies of 10-substituted 2-(1-piperazinyl)pyrimido[1,2-a]benzimidazol-4(10H)-ones. Di Braccio M, Grossi G, Signorello MG, Leoncini G, Cichero E, Fossa P, Alfei S, Damonte G. Eur J Med Chem 62 564-578 (2013)
  30. Charting the interactome of PDE3A in human cells using an IBMX based chemical proteomics approach. Corradini E, Klaasse G, Leurs U, Heck AJ, Martin NI, Scholten A. Mol Biosyst 11 2786-2797 (2015)
  31. Surface Binding Energy Landscapes Affect Phosphodiesterase Isoform-Specific Inhibitor Selectivity. Liu Q, Herrmann A, Huang Q. Comput Struct Biotechnol J 17 101-109 (2019)
  32. Modulating the cyclic guanosine monophosphate substrate selectivity of the phosphodiesterase 3 inhibitors by pyridine, pyrido[2,3-d]pyrimidine derivatives and their effects upon the growth of HT-29 cancer cell line. Abadi AH, Hany MS, Elsharif SA, Eissa AA, Gary BD, Tinsley HN, Piazza GA. Chem Pharm Bull (Tokyo) 61 405-410 (2013)
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  34. Anagrelide: A Clinically Effective cAMP Phosphodiesterase 3A Inhibitor with Molecular Glue Properties. Meanwell NA. ACS Med Chem Lett 14 350-361 (2023)
  35. Discovery of Potent, Selective Triazolothiadiazole-Containing c-Met Inhibitors. Tang Q, Aronov AM, Deininger DD, Giroux S, Lauffer DJ, Li P, Liang J, McGinty K, Ronkin S, Swett R, Waal N, Boucher D, Ford PJ, Moody CS. ACS Med Chem Lett 12 955-960 (2021)


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