ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Figure 1Loading Img

The Crystal Structure of AMP-Bound PDE4 Suggests a Mechanism for Phosphodiesterase Catalysis,

View Author Information
Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina 27599-7260, and Department of Biological Chemistry and Molecular Biology Institute, University of California at Los Angeles School of Medicine, Los Angeles, California 90095-1737
Cite this: Biochemistry 2003, 42, 45, 13220–13226
Publication Date (Web):October 25, 2003
Copyright © 2003 American Chemical Society

    Article Views





    Other access options


    Cyclic nucleotide phosphodiesterases (PDEs) regulate the intracellular concentrations of cyclic 3‘,5‘-adenosine and guanosine monophosphates (cAMP and cGMP, respectively) by hydrolyzing them to AMP and GMP, respectively. Family-selective inhibitors of PDEs have been studied for treatment of various human diseases. However, the catalytic mechanism of cyclic nucleotide hydrolysis by PDEs has remained unclear. We determined the crystal structure of the human PDE4D2 catalytic domain in complex with AMP at 2.4 Å resolution. In this structure, two divalent metal ions simultaneously interact with the phosphate group of AMP, implying a binuclear catalysis. In addition, the structure suggested that a hydroxide ion or a water bridging two metal ions may serve as the nucleophile for the hydrolysis of the cAMP phosphodiester bond.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.


    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

     This work was supported in part by NIH Grants GM59791 to H.K. and NS31911 to J.C.

     The coordinates have been deposited in the Protein Data Bank as entry 1PTW.


     The University of North Carolina.

     University of California.


     To whom correspondence should be addressed. Phone:  (919) 966-2244. Fax:  (919) 966-2852. E-mail:  [email protected].

    Cited By

    This article is cited by 109 publications.

    1. Richard S. Roberts, Sara Sevilla, Manel Ferrer, Joan Taltavull, Begoña Hernández, Victor Segarra, Jordi Gràcia, Martin D. Lehner, Amadeu Gavaldà, Miriam Andrés, Judit Cabedo, Dolors Vilella, Peter Eichhorn, Elena Calama, Carla Carcasona, Montserrat Miralpeix. 4-Amino-7,8-dihydro-1,6-naphthyridin-5(6H)-ones as Inhaled Phosphodiesterase Type 4 (PDE4) Inhibitors: Structural Biology and Structure–Activity Relationships. Journal of Medicinal Chemistry 2018, 61 (6) , 2472-2489.
    2. Jordi Gràcia, Maria Antonia Buil, Jordi Castro, Peter Eichhorn, Manel Ferrer, Amadeu Gavaldà, Begoña Hernández, Victor Segarra, Martin D. Lehner, Imma Moreno, Lluís Pagès, Richard S. Roberts, Jordi Serrat, Sara Sevilla, Joan Taltavull, Miriam Andrés, Judit Cabedo, Dolors Vilella, Elena Calama, Carla Carcasona, and Montserrat Miralpeix . Biphenyl Pyridazinone Derivatives as Inhaled PDE4 Inhibitors: Structural Biology and Structure–Activity Relationships. Journal of Medicinal Chemistry 2016, 59 (23) , 10479-10497.
    3. Chimed Jansen, Albert J. Kooistra, Georgi K. Kanev, Rob Leurs, Iwan J. P. de Esch, and Chris de Graaf . PDEStrIAn: A Phosphodiesterase Structure and Ligand Interaction Annotated Database As a Tool for Structure-Based Drug Design. Journal of Medicinal Chemistry 2016, 59 (15) , 7029-7065.
    4. Zhe Li, Yinuo Wu, Ling-Jun Feng, Ruibo Wu, and Hai-Bin Luo . Ab Initio QM/MM Study Shows a Highly Dissociated SN2 Hydrolysis Mechanism for the cGMP-Specific Phosphodiesterase-5. Journal of Chemical Theory and Computation 2014, 10 (12) , 5448-5457.
    5. Yuanyuan Tian, Wenjun Cui, Manna Huang, Howard Robinson, Yiqian Wan, Yousheng Wang, and Hengming Ke . Dual Specificity and Novel Structural Folding of Yeast Phosphodiesterase-1 for Hydrolysis of Second Messengers Cyclic Adenosine and Guanosine 3′,5′-Monophosphate. Biochemistry 2014, 53 (30) , 4938-4945.
    6. Xi Chen, Xinyun Zhao, Ying Xiong, Junjun Liu, and Chang-Guo Zhan . Fundamental Reaction Pathway and Free Energy Profile for Hydrolysis of Intracellular Second Messenger Adenosine 3′,5′-Cyclic Monophosphate (cAMP) Catalyzed by Phosphodiesterase-4. The Journal of Physical Chemistry B 2011, 115 (42) , 12208-12219.
    7. Jung Mee Park and Mauro Boero. Protonation of a Hydroxide Anion Bridging Two Divalent Magnesium Cations in Water Probed by First-Principles Metadynamics Simulation. The Journal of Physical Chemistry B 2010, 114 (34) , 11102-11109.
    8. Justin Kai-Chi Lau, Xiao-Bo Li and Yuen-Kit Cheng. A Substrate Selectivity and Inhibitor Design Lesson from the PDE10−cAMP Crystal Structure: A Computational Study. The Journal of Physical Chemistry B 2010, 114 (15) , 5154-5160.
    9. Huanchen Wang, Xuan Luo, Mengchun Ye, Jing Hou, Howard Robinson and Hengming Ke . Insight into Binding of Phosphodiesterase-9A Selective Inhibitors by Crystal Structures and Mutagenesis. Journal of Medicinal Chemistry 2010, 53 (4) , 1726-1731.
    10. Dandamudi Usharani, Palakuri Srivani, G. Narahari Sastry and Eluvathingal D. Jemmis . pH Dependence of a 310-Helix versus a Turn in the M-Loop Region of PDE4: Observations on PDB Entries and an Electronic Structure Study. Journal of Chemical Theory and Computation 2008, 4 (6) , 974-984.
    11. Roya Zoraghi,, Sharron H. Francis, and, Jackie D. Corbin. Critical Amino Acids in Phosphodiesterase-5 Catalytic Site That Provide for High-Affinity Interaction with Cyclic Guanosine Monophosphate and Inhibitors. Biochemistry 2007, 46 (47) , 13554-13563.
    12. E. Alan Salter and, Andrzej Wierzbicki. The Mechanism of Cyclic Nucleotide Hydrolysis in the Phosphodiesterase Catalytic Site. The Journal of Physical Chemistry B 2007, 111 (17) , 4547-4552.
    13. Qing Huai,, Yingjie Sun,, Huanchen Wang,, Dwight Macdonald,, Renée Aspiotis,, Howard Robinson,, Zheng Huang, and, Hengming Ke. Enantiomer Discrimination Illustrated by the High Resolution Crystal Structures of Type 4 Phosphodiesterase. Journal of Medicinal Chemistry 2006, 49 (6) , 1867-1873.
    14. André Iffland,, Darcy Kohls,, Simon Low,, Jing Luan,, Yan Zhang,, Michael Kothe,, Qing Cao,, Ajith V. Kamath,, Yuan-Hua Ding, and, Tom Ellenberger. Structural Determinants for Inhibitor Specificity and Selectivity in PDE2A Using the Wheat Germ in Vitro Translation System. Biochemistry 2005, 44 (23) , 8312-8325.
    15. Mireille Krier,, João X. de Araújo-Júnior,, Martine Schmitt,, Jérôme Duranton,, Hélène Justiano-Basaran,, Claire Lugnier,, Jean-Jacques Bourguignon, and, Didier Rognan. Design of Small-Sized Libraries by Combinatorial Assembly of Linkers and Functional Groups to a Given Scaffold: Application to the Structure-Based Optimization of a Phosphodiesterase 4 Inhibitor. Journal of Medicinal Chemistry 2005, 48 (11) , 3816-3822.
    16. David T. Manallack,, Richard A. Hughes, and, Philip E. Thompson. The Next Generation of Phosphodiesterase Inhibitors:  Structural Clues to Ligand and Substrate Selectivity of Phosphodiesterases. Journal of Medicinal Chemistry 2005, 48 (10) , 3449-3462.
    17. Paola Gratteri,, Claudia Bonaccini, and, Fabrizio Melani. Searching for a Reliable Orientation of Ligands in Their Binding Site:  Comparison between a Structure-Based (Glide) and a Ligand-Based (FIGO) Approach in the Case Study of PDE4 Inhibitors. Journal of Medicinal Chemistry 2005, 48 (5) , 1657-1665.
    18. Giovanna Scapin,, Sangita B. Patel,, Christine Chung,, Jeffrey P. Varnerin,, Scott D. Edmondson,, Anthony Mastracchio,, Emma R. Parmee,, Suresh B. Singh,, Joseph W. Becker,, Lex H. T. Van der Ploeg, and, Michael R. Tota. Crystal Structure of Human Phosphodiesterase 3B:  Atomic Basis for Substrate and Inhibitor Specificity. Biochemistry 2004, 43 (20) , 6091-6100.
    19. Louise F. Dow, Alfie M. Case, Megan P. Paustian, Braeden R. Pinkerton, Princess Simeon, Paul C. Trippier. The evolution of small molecule enzyme activators. RSC Medicinal Chemistry 2023, 14 (11) , 2206-2230.
    20. Dhritiman Roy, Shivaramakrishnan Balasubramanian, Praveen Thaggikuppe Krishnamurthy, Piyong Sola, Emdormi Rymbai. Phosphodiesterase-4 Inhibition in Parkinson’s Disease: Molecular Insights and Therapeutic Potential. Cellular and Molecular Neurobiology 2023, 43 (6) , 2713-2741.
    21. Xuemei Wei, Guoqi Yu, Hualiang Shen, Yanjuan Luo, Tianbo Shang, Runpu Shen, Meiyang Xi, Haopeng Sun. Targeting phosphodiesterase 4 as a therapeutic strategy for cognitive improvement. Bioorganic Chemistry 2023, 130 , 106278.
    22. Mutyala Satish, Kumari Sandhya, Kulhar Nitin, Ninjoor Yashas Kiran, Babu Aleena, Adiga Satish Kumar, Kalthur G, Eerappa Rajakumara. Computational, biochemical and ex vivo evaluation of xanthine derivatives against phosphodiesterases to enhance the sperm motility. Journal of Biomolecular Structure and Dynamics 2022, 11 , 1-11.
    23. Khaled M. Darwish, Ahmad Abdelwaly, Asmaa M. Atta, Mohamed A. Helal. Discovery of tetrahydro-β-carboline- and indole-based derivatives as promising phosphodiesterase-4 inhibitors: Synthesis, biological evaluation, and molecular modeling studies. Journal of Molecular Structure 2022, 1248 , 131491.
    24. Ilkay Erdogan Orhan, Abdur Rauf, Muhammad Saleem, Anees Ahmed Khalil. Natural Molecules as Talented Inhibitors of Nucleotide Pyrophosphatases/ Phosphodiesterases (PDEs). Current Topics in Medicinal Chemistry 2022, 22 (3) , 209-228.
    25. Colin W. Garvie, Xiaoyun Wu, Malvina Papanastasiou, Sooncheol Lee, James Fuller, Gavin R. Schnitzler, Steven W. Horner, Andrew Baker, Terry Zhang, James P. Mullahoo, Lindsay Westlake, Stephanie H. Hoyt, Marcus Toetzl, Matthew J. Ranaghan, Luc de Waal, Joseph McGaunn, Bethany Kaplan, Federica Piccioni, Xiaoping Yang, Martin Lange, Adrian Tersteegen, Donald Raymond, Timothy A. Lewis, Steven A. Carr, Andrew D. Cherniack, Christopher T. Lemke, Matthew Meyerson, Heidi Greulich. Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase. Nature Communications 2021, 12 (1)
    26. Elizabeth R. Morris, Sarah J. Caswell, Simone Kunzelmann, Laurence H. Arnold, Andrew G. Purkiss, Geoff Kelly, Ian A. Taylor. Crystal structures of SAMHD1 inhibitor complexes reveal the mechanism of water-mediated dNTP hydrolysis. Nature Communications 2020, 11 (1)
    27. Abid Bhat, Bipul Ray, Arehally Marappa Mahalakshmi, Sunanda Tuladhar, DN Nandakumar, Malathi Srinivasan, Musthafa Mohamed Essa, Saravana Babu Chidambaram, Gilles J. Guillemin, Meena Kishore Sakharkar. Phosphodiesterase-4 enzyme as a therapeutic target in neurological disorders. Pharmacological Research 2020, 160 , 105078.
    28. Mayasah Al-Nema, Anand Gaurav, Vannajan Sanghiran Lee. Docking based screening and molecular dynamics simulations to identify potential selective PDE4B inhibitor. Heliyon 2020, 6 (9) , e04856.
    29. Nirakar Adhikari, Nick A. Kuburich, Jeffrey A. Hadwiger. Mitogen-activated protein kinase regulation of the phosphodiesterase RegA in early Dictyostelium development. Microbiology 2020, 166 (2) , 129-140.
    30. Yixian Liao, Xiuhua Jia, Yongmei Tang, Sumei Li, Yipeng Zang, Lei Wang, Zi-Ning Cui, Gaopeng Song. Discovery of novel inhibitors of phosphodiesterase 4 with 1-phenyl-3,4-dihydroisoquinoline scaffold: Structure-based drug design and fragment identification. Bioorganic & Medicinal Chemistry Letters 2019, 29 (22) , 126720.
    31. Kevin D. Schuster, Mohammadjavad Mohammadi, Karyn B. Cahill, Suzanne L. Matte, Alexis D. Maillet, Harish Vashisth, Rick H. Cote, . Pharmacological and molecular dynamics analyses of differences in inhibitor binding to human and nematode PDE4: Implications for management of parasitic nematodes. PLOS ONE 2019, 14 (3) , e0214554.
    32. Ahmad Abdelwaly, Ismail Salama, Mohamed S. Gomaa, Mohamed A. Helal. Discovery of tetrahydro-ß-carboline derivatives as a new class of phosphodiesterase 4 inhibitors. Medicinal Chemistry Research 2017, 26 (12) , 3173-3187.
    33. Yousheng Wang, Hengming Ke. A Unique Sub-Pocket for Improvement of Selectivity of Phosphodiesterase Inhibitors in CNS. 2017, 463-471.
    34. Naga Srinivas Tripuraneni, Mohammed Afzal Azam. A combination of pharmacophore modeling, atom-based 3D-QSAR, molecular docking and molecular dynamics simulation studies on PDE4 enzyme inhibitors. Journal of Biomolecular Structure and Dynamics 2016, 34 (11) , 2481-2492.
    35. Lauren Wills, Munisah Ehsan, Ellanor L. Whiteley, George S. Baillie. Location, location, location: PDE4D5 function is directed by its unique N-terminal region. Cellular Signalling 2016, 28 (7) , 701-705.
    36. Inonge Gross, Jörg Durner. In Search of Enzymes with a Role in 3′, 5′-Cyclic Guanosine Monophosphate Metabolism in Plants. Frontiers in Plant Science 2016, 7
    37. Naga Srinivas Tripuraneni, Mohammed Afzal Azam. Pharmacophore modeling, 3D-QSAR and docking study of 2-phenylpyrimidine analogues as selective PDE4B inhibitors. Journal of Theoretical Biology 2016, 394 , 117-126.
    38. David Thomae, Stijn Servaes, Naiara Vazquez, Leonie wyffels, Stefanie Dedeurwaerdere, Pieter Van der Veken, Jurgen Joossens, Koen Augustyns, Sigrid Stroobants, Steven Staelens. Synthesis and preclinical evaluation of an 18 F labeled PDE7 inhibitor for PET neuroimaging. Nuclear Medicine and Biology 2015, 42 (12) , 975-981.
    39. Naga Srinivas Tripuraneni, Mohammed Afzal Azam. Pharmacophore modeling, 3D-QSAR, and docking study of pyrozolo[1,5-a]pyridine/4,4-dimethylpyrazolone analogues as PDE4 selective inhibitors. Journal of Molecular Modeling 2015, 21 (11)
    40. Hengming Ke, Huanchen Wang, Mengchun Ye, Yingchun Huang. Crystal Structures of Phosphodiesterases and Implication on Discovery of Inhibitors. 2014, 145-170.
    41. Jayvardhan Pandit. PDE4: New Structural Insights into the Regulatory Mechanism and Implications for the Design of Selective Inhibitors. 2014, 29-44.
    42. Donald H. Maurice, Hengming Ke, Faiyaz Ahmad, Yousheng Wang, Jay Chung, Vincent C. Manganiello. Advances in targeting cyclic nucleotide phosphodiesterases. Nature Reviews Drug Discovery 2014, 13 (4) , 290-314.
    43. D J P Henderson, A Byrne, K Dulla, G Jenster, R Hoffmann, G S Baillie, M D Houslay. The cAMP phosphodiesterase-4D7 (PDE4D7) is downregulated in androgen-independent prostate cancer cells and mediates proliferation by compartmentalising cAMP at the plasma membrane of VCaP prostate cancer cells. British Journal of Cancer 2014, 110 (5) , 1278-1287.
    44. Susanne C. Feil, Jessica K. Holien, Craig J. Morton, Nancy C. Hancock, Philip E. Thompson, Michael W. Parker. Discovery of Phosphodiesterase-4 Inhibitors: Serendipity and Rational Drug Design. Australian Journal of Chemistry 2014, 67 (12) , 1780.
    45. Manel Ferrer, Richard S. Roberts, Sara Sevilla. A modular synthesis of novel 4-amino-7,8-dihydro-1,6-naphthyridin-5(6H)-ones as PDE4 inhibitors. Tetrahedron Letters 2013, 54 (36) , 4821-4825.
    46. Amadeu Gavaldà, Richard S Roberts. Phosphodiesterase-4 inhibitors: a review of current developments (2010 – 2012). Expert Opinion on Therapeutic Patents 2013, 23 (8) , 997-1016.
    47. Danielle C. Lynch, David A. Dyment, Lijia Huang, Sarah M. Nikkel, Didier Lacombe, Philippe M. Campeau, Brendan Lee, Carlos A. Bacino, Jacques L. Michaud, Francois P. Bernier, FORGE Canada Consortium, Jillian S. Parboosingh, A. Micheil Innes. Identification of Novel Mutations Confirms Pde4d as a Major Gene Causing Acrodysostosis. Human Mutation 2013, 34 (1) , 97-102.
    48. Justin Kai‐Chi Lau, Yuen‐Kit Cheng. An update view on the substrate recognition mechanism of phosphodiesterases: A computational study of PDE10 and PDE4 bound with cyclic nucleotides. Biopolymers 2012, 97 (11) , 910-922.
    50. Michael I. Recht, Vandana Sridhar, John Badger, Leslie Hernandez, Barbara Chie-Leon, Vicki Nienaber, Francisco E. Torres. Fragment-Based Screening for Inhibitors of PDE4A Using Enthalpy Arrays and X-ray Crystallography. SLAS Discovery 2012, 17 (4) , 469-480.
    51. Jacob L. Nankervis, Susanne C. Feil, Nancy C. Hancock, Zhaohua Zheng, Hooi-Ling Ng, Craig J. Morton, Jessica K. Holien, Patricia W.M. Ho, Mark M. Frazzetto, Ian G. Jennings, David T. Manallack, T. John Martin, Philip E. Thompson, Michael W. Parker. Thiophene inhibitors of PDE4: Crystal structures show a second binding mode at the catalytic domain of PDE4D2. Bioorganic & Medicinal Chemistry Letters 2011, 21 (23) , 7089-7093.
    52. Brooke L. Fridley, Anthony Batzler, Liang Li, Fang Li, Alice Matimba, Gregory D. Jenkins, Yuan Ji, Liewei Wang, Richard M. Weinshilboum. Gene set analysis of purine and pyrimidine antimetabolites cancer therapies. Pharmacogenetics and Genomics 2011, 21 (11) , 701-712.
    53. Andrew L. Lovering, Michael J. Capeness, Carey Lambert, Laura Hobley, R. Elizabeth Sockett, . The Structure of an Unconventional HD-GYP Protein from Bdellovibrio Reveals the Roles of Conserved Residues in this Class of Cyclic-di-GMP Phosphodiesterases. mBio 2011, 2 (5)
    54. Ivan I. Vorontsov, George Minasov, Olga Kiryukhina, Joseph S. Brunzelle, Ludmilla Shuvalova, Wayne F. Anderson. Characterization of the Deoxynucleotide Triphosphate Triphosphohydrolase (dNTPase) Activity of the EF1143 Protein from Enterococcus faecalis and Crystal Structure of the Activator-Substrate Complex. Journal of Biological Chemistry 2011, 286 (38) , 33158-33166.
    55. Kin‐Yiu Wong, Jiali Gao. Insight into the phosphodiesterase mechanism from combined QM/MM free energy simulations. The FEBS Journal 2011, 278 (14) , 2579-2595.
    56. Sharron H. Francis, Mitsi A. Blount, Jackie D. Corbin. Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions. Physiological Reviews 2011, 91 (2) , 651-690.
    57. Hengming Ke, Huanchen Wang, Mengchun Ye. Structural Insight into the Substrate Specificity of Phosphodiesterases. 2011, 121-134.
    58. Anatoli Tchigvintsev, Xiaohui Xu, Alexander Singer, Changsoo Chang, Greg Brown, Michael Proudfoot, Hong Cui, Robert Flick, Wayne F. Anderson, Andrzej Joachimiak, Michael Y. Galperin, Alexei Savchenko, Alexander F. Yakunin. Structural Insight into the Mechanism of c-di-GMP Hydrolysis by EAL Domain Phosphodiesterases. Journal of Molecular Biology 2010, 402 (3) , 524-538.
    59. Miles Houslay, Marco Conti. Phosphodiesterase 4D, cAMP specific. AfCS-Nature Molecule Pages 2010,
    60. György G. Ferenczy. Application of Molecular Modeling in Analogue‐Based Drug Discovery. 2010, 61-82.
    61. Jong-Rim Bae, Jeong-Koo Kim, Chang-Woo Lee. Complex Formation of Adenosine 3',5'-Cyclic Monophosphate with β-Cyclodextrin: Kinetics and Mechanism by Ultrasonic Relaxation. Bulletin of the Korean Chemical Society 2010, 31 (2) , 442-446.
    62. Jayvardhan Pandit, Michael D. Forman, Kimberly F. Fennell, Keith S. Dillman, Frank S. Menniti. Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct. Proceedings of the National Academy of Sciences 2009, 106 (43) , 18225-18230.
    63. Kohei Kagayama, Tatsuya Morimoto, Seigo Nagata, Fumitaka Katoh, Xin Zhang, Naoki Inoue, Asami Hashino, Kiyoto Kageyama, Jiro Shikaura, Tomoko Niwa. Synthesis and biological evaluation of novel phthalazinone derivatives as topically active phosphodiesterase 4 inhibitors. Bioorganic & Medicinal Chemistry 2009, 17 (19) , 6959-6970.
    64. James L. Weeks, Jackie D. Corbin, Sharron H. Francis. Interactions between Cyclic Nucleotide Phosphodiesterase 11 Catalytic Site and Substrates or Tadalafil and Role of a Critical Gln-869 Hydrogen Bond. Journal of Pharmacology and Experimental Therapeutics 2009, 331 (1) , 133-141.
    65. Amanda P. Skoumbourdis, Christopher A. LeClair, Eduard Stefan, Adrian G. Turjanski, William Maguire, Steven A. Titus, Ruili Huang, Douglas S. Auld, James Inglese, Christopher P. Austin, Stephen W. Michnick, Menghang Xia, Craig J. Thomas. Exploration and optimization of substituted triazolothiadiazines and triazolopyridazines as PDE4 inhibitors. Bioorganic & Medicinal Chemistry Letters 2009, 19 (13) , 3686-3692.
    66. Ryosuke Mega, Naoyuki Kondo, Noriko Nakagawa, Seiki Kuramitsu, Ryoji Masui. Two dNTP triphosphohydrolases from Pseudomonas aeruginosa possess diverse substrate specificities. The FEBS Journal 2009, 276 (12) , 3211-3221.
    67. Zier Yan, Huanchen Wang, Jiwen Cai, Hengming Ke. Refolding and kinetic characterization of the phosphodiesterase-8A catalytic domain. Protein Expression and Purification 2009, 64 (1) , 82-88.
    68. Jeremy M. Murray, Dirksen E. Bussiere. Targeting the Purinome. 2009, 47-92.
    69. Shenping Liu, Mahmoud N. Mansour, Keith S. Dillman, Jose R. Perez, Dennis E. Danley, Paul A. Aeed, Samuel P. Simons, Peter K. LeMotte, Frank S. Menniti. Structural basis for the catalytic mechanism of human phosphodiesterase 9. Proceedings of the National Academy of Sciences 2008, 105 (36) , 13309-13314.
    70. Tsung-Yu Chen, Tzyh-Chang Hwang. CLC-0 and CFTR: Chloride Channels Evolved From Transporters. Physiological Reviews 2008, 88 (2) , 351-387.
    71. Naoyuki Kondo, Takashi Nishikubo, Taisuke Wakamatsu, Hirohito Ishikawa, Noriko Nakagawa, Seiki Kuramitsu, Ryoji Masui. Insights into different dependence of dNTP triphosphohydrolase on metal ion species from intracellular ion concentrations in Thermus thermophilus. Extremophiles 2008, 12 (2) , 217-223.
    72. E. A. Salter, Kerrie A. O'Brien, R. Wesley Edmunds, A. Wierzbicki. ONIOM investigation of nucleotide selectivity in phosphodiesterases 3 and 4. International Journal of Quantum Chemistry 2008, 108 (6) , 1189-1199.
    73. Nam-Sook Kang, Seok-Joo Hong, Chong-Hak Chae, Sung-Eun Yoo. Comparative molecular field analysis (CoMFA) for phosphodiesterase (PDE) IV inhibitors. Journal of Molecular Structure: THEOCHEM 2007, 820 (1-3) , 58-64.
    74. Huanchen Wang, Howard Robinson, Hengming Ke. The Molecular Basis for Different Recognition of Substrates by Phosphodiesterase Families 4 and 10. Journal of Molecular Biology 2007, 371 (2) , 302-307.
    75. Marco Conti, Joseph Beavo. Biochemistry and Physiology of Cyclic Nucleotide Phosphodiesterases: Essential Components in Cyclic Nucleotide Signaling. Annual Review of Biochemistry 2007, 76 (1) , 481-511.
    76. Huanchen Wang, Yudong Liu, Jing Hou, Meiyan Zheng, Howard Robinson, Hengming Ke. Structural insight into substrate specificity of phosphodiesterase 10. Proceedings of the National Academy of Sciences 2007, 104 (14) , 5782-5787.
    77. Kerrie A. O'Brien, E. A. Salter, A. Wierzbicki. ONIOM quantum chemistry study of cyclic nucleotide recognition in phosphodiesterase 5. International Journal of Quantum Chemistry 2007, 107 (12) , 2197-2203.
    78. M.M. Flocco, D.G. Brown, A. Pannifer. Enzymes: Insights for Drug Design from Structure. 2007, 749-766.
    79. Huanchen Wang, Hengming Ke. Structure, Catalytic Mechanism, and Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases. 2006
    80. Sharron Francis, Roya Zoraghi, Jun Kotera, Hengming Ke, Emmanuel Bessay, Mitsi Blount, Jackie Corbin. Phosphodiesterase 5. 2006
    81. Kam Zhang. Crystal Structure of Phosphodiesterase Families and the Potential for Rational Drug Design. 2006
    82. Franc Meyer. Clues to Dimetallohydrolase Mechanisms from Studies on Pyrazolate‐Based Bioinspired Dizinc Complexes – Experimental Evidence for a Functional Zn–O 2 H 3 –Zn Motif. European Journal of Inorganic Chemistry 2006, 2006 (19) , 3789-3800.
    83. Zhen Zhou, Xiaohui Wang, Hao-Yang Liu, Xiaoqin Zou, Min Li, Tzyh-Chang Hwang. The Two ATP Binding Sites of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Play Distinct Roles in Gating Kinetics and Energetics. The Journal of General Physiology 2006, 128 (4) , 413-422.
    84. Andrew T. Bender, Joseph A. Beavo. Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use. Pharmacological Reviews 2006, 58 (3) , 488-520.
    85. Graeme B. Bolger, George S. Baillie, Xiang Li, Martin J. Lynch, Pawel Herzyk, Ahmed Mohamed, Lisa High Mitchell, Angela McCahill, Christian Hundsrucker, Enno Klussmann, David R. Adams, Miles D. Houslay. Scanning peptide array analyses identify overlapping binding sites for the signalling scaffold proteins, β-arrestin and RACK1, in cAMP-specific phosphodiesterase PDE4D5. Biochemical Journal 2006, 398 (1) , 23-36.
    86. Johnjeff Alvarado, Anita Ghosh, Tyler Janovitz, Andrew Jauregui, Miriam S. Hasson, David Avram Sanders. Origin of Exopolyphosphatase Processivity: Fusion of an ASKHA Phosphotransferase and a Cyclic Nucleotide Phosphodiesterase Homolog. Structure 2006, 14 (8) , 1263-1272.
    87. Jie-Fei Cheng, Chi Ching Mak, Yujin Huang, Richard Penuliar, Masahiro Nishimoto, Lin Zhang, Mi Chen, David Wallace, Thomas Arrhenius, Donald Chu, Guang Yang, Miguel Barbosa, Rick Barr, Jason R.B. Dyck, Gary D. Lopaschuk, Alex M. Nadzan. Heteroaryl substituted bis-trifluoromethyl carbinols as malonyl-CoA decarboxylase inhibitors. Bioorganic & Medicinal Chemistry Letters 2006, 16 (13) , 3484-3488.
    88. Huanchen Wang, Yudong Liu, Qing Huai, Jiwen Cai, Roya Zoraghi, Sharron H. Francis, Jackie D. Corbin, Howard Robinson, Zhongcheng Xin, Guiting Lin, Hengming Ke. Multiple Conformations of Phosphodiesterase-5. Journal of Biological Chemistry 2006, 281 (30) , 21469-21479.
    89. Vsevolod V. Gurevich, Eugenia V. Gurevich. The structural basis of arrestin-mediated regulation of G-protein-coupled receptors. Pharmacology & Therapeutics 2006, 110 (3) , 465-502.
    90. N. S. Kang, C. H. Chae, S.-E. Yoo. Study on the hydrolysis mechanism of phosphodiesterase 4 using molecular dynamics simulations. Molecular Simulation 2006, 32 (5) , 369-374.
    91. Claire Lugnier. Cyclic nucleotide phosphodiesterase (PDE) superfamily: A new target for the development of specific therapeutic agents. Pharmacology & Therapeutics 2006, 109 (3) , 366-398.
    92. Roya Zoraghi, Jackie D. Corbin, Sharron H. Francis. Phosphodiesterase-5 Gln817 Is Critical for cGMP, Vardenafil, or Sildenafil Affinity. Journal of Biological Chemistry 2006, 281 (9) , 5553-5558.
    93. Miles Houslay. Phosphodiesterase 4A, cAMP specific. AfCS-Nature Molecule Pages 2006,
    94. Miles Houslay. Phosphodiesterase 4B, cAMP specific. AfCS-Nature Molecule Pages 2006,
    95. Martin J. Lynch, Elaine V. Hill, Miles D. Houslay. Intracellular Targeting of Phosphodiesterase‐4 Underpins Compartmentalized cAMP Signaling. 2006, 225-259.
    96. Kam YJ Zhang, Prabha N Ibrahim, Sam Gillette, Gideon Bollag. Phosphodiesterase-4 as a potential drug target. Expert Opinion on Therapeutic Targets 2005, 9 (6) , 1283-1305.
    97. Zhen Zhou, Xiaohui Wang, Min Li, Yoshiro Sohma, Xiaoqin Zou, Tzyh‐Chang Hwang. High affinity ATP/ADP analogues as new tools for studying CFTR gating. The Journal of Physiology 2005, 569 (2) , 447-457.
    98. Huanchen Wang, Yudong Liu, Yuxiang Chen, Howard Robinson, Hengming Ke. Multiple Elements Jointly Determine Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases 4 and 7. Journal of Biological Chemistry 2005, 280 (35) , 30949-30955.
    99. Bernhard Bauer‐Siebenlist, Franc Meyer, Etelka Farkas, Denis Vidovic, Sebastian Dechert. Effect of Zn⋅⋅⋅Zn Separation on the Hydrolytic Activity of Model Dizinc Phosphodiesterases. Chemistry – A European Journal 2005, 11 (15) , 4349-4360.
    100. Joshua O Odingo. Inhibitors of PDE4: a review of recent patent literature. Expert Opinion on Therapeutic Patents 2005, 15 (7) , 773-787.
    Load all citations

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Your Mendeley pairing has expired. Please reconnect