Hengming Ke

Summary

Affiliation: University of North Carolina
Country: USA

Publications

  1. doi request reprint Structural insight into the substrate specificity of phosphodiesterases
    Hengming Ke
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599 7260, USA
    Handb Exp Pharmacol . 2011
  2. pmc Structural asymmetry of phosphodiesterase-9, potential protonation of a glutamic acid, and role of the invariant glutamine
    Jing Hou
    Structural Biology Lab, School of Pharmaceutical Sciences, Sun Yat Sen University, Guangzhou, People s Republic of China
    PLoS ONE 6:e18092. 2011
  3. ncbi request reprint Crystal structures of cyclophilin and its partners
    Hengming Ke
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599 7260, USA
    Front Biosci 9:2285-96. 2004
  4. ncbi request reprint Crystal structures of phosphodiesterases and implications on substrate specificity and inhibitor selectivity
    Hengming Ke
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599 7260, USA
    Curr Top Med Chem 7:391-403. 2007
  5. ncbi request reprint Structures of calcineurin and its complexes with immunophilins-immunosuppressants
    Hengming Ke
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599 7260, USA
    Biochem Biophys Res Commun 311:1095-102. 2003
  6. pmc Structural insight into substrate specificity of phosphodiesterase 10
    Huanchen Wang
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599 7260, USA
    Proc Natl Acad Sci U S A 104:5782-7. 2007
  7. pmc An insight into the pharmacophores of phosphodiesterase-5 inhibitors from synthetic and crystal structural studies
    Gong Chen
    School of Chemistry and Chemical Engineering, Center of Structure Biology, School of Pharmaceutical Sciences, Sun Yat Sen University, Guangzhou 510275, PR China
    Biochem Pharmacol 75:1717-28. 2008
  8. pmc Crystal structure of phosphodiesterase 9 shows orientation variation of inhibitor 3-isobutyl-1-methylxanthine binding
    Qing Huai
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599 7260, USA
    Proc Natl Acad Sci U S A 101:9624-9. 2004
  9. pmc Biological and structural characterization of Trypanosoma cruzi phosphodiesterase C and Implications for design of parasite selective inhibitors
    Huanchen Wang
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599 7260, USA
    J Biol Chem 287:11788-97. 2012
  10. pmc Computer-based redesign of a beta sandwich protein suggests that extensive negative design is not required for de novo beta sheet design
    Xiaozhen Hu
    Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 7260, USA
    Structure 16:1799-805. 2008

Collaborators

Detail Information

Publications38

  1. doi request reprint Structural insight into the substrate specificity of phosphodiesterases
    Hengming Ke
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599 7260, USA
    Handb Exp Pharmacol . 2011
    ..Therefore, the substrate specificity of PDEs is likely to be determined jointly by multiple elements at the active site, yet the detailed mechanism needs further study...
  2. pmc Structural asymmetry of phosphodiesterase-9, potential protonation of a glutamic acid, and role of the invariant glutamine
    Jing Hou
    Structural Biology Lab, School of Pharmaceutical Sciences, Sun Yat Sen University, Guangzhou, People s Republic of China
    PLoS ONE 6:e18092. 2011
    ..The information from these studies may be useful for design of PDE9 inhibitors...
  3. ncbi request reprint Crystal structures of cyclophilin and its partners
    Hengming Ke
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599 7260, USA
    Front Biosci 9:2285-96. 2004
    ..The structures of the binary CyPA-CsA and ternary CN-CyPA-CsA complexes showed how CsA binds to its receptors and therefore provide a template for design of new immunosuppressive drugs...
  4. ncbi request reprint Crystal structures of phosphodiesterases and implications on substrate specificity and inhibitor selectivity
    Hengming Ke
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599 7260, USA
    Curr Top Med Chem 7:391-403. 2007
    ..The kinetic analysis on the mutations of PDE7 to PDE4 suggests that the multiple elements must work together to define inhibitor selectivity...
  5. ncbi request reprint Structures of calcineurin and its complexes with immunophilins-immunosuppressants
    Hengming Ke
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599 7260, USA
    Biochem Biophys Res Commun 311:1095-102. 2003
    ..The recognition site and the active site are adjacent and form an "L" shaped cleft. This implies that the immunophilin recognition site may also serve as a recognition site to define the narrow substrate specificity of calcineurin...
  6. pmc Structural insight into substrate specificity of phosphodiesterase 10
    Huanchen Wang
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599 7260, USA
    Proc Natl Acad Sci U S A 104:5782-7. 2007
    ..Sequence alignment shows a potential pocket, in which variation of amino acids across PDE families defines the size and shape of the pocket and thus determines the substrate specificity...
  7. pmc An insight into the pharmacophores of phosphodiesterase-5 inhibitors from synthetic and crystal structural studies
    Gong Chen
    School of Chemistry and Chemical Engineering, Center of Structure Biology, School of Pharmaceutical Sciences, Sun Yat Sen University, Guangzhou 510275, PR China
    Biochem Pharmacol 75:1717-28. 2008
    ..However, the PDE5-12 structure does not provide a full explanation to affinity changes of the inhibitors. Thus alternatives such as conformational change of the M-loop are open and further structural study is required...
  8. pmc Crystal structure of phosphodiesterase 9 shows orientation variation of inhibitor 3-isobutyl-1-methylxanthine binding
    Qing Huai
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599 7260, USA
    Proc Natl Acad Sci U S A 101:9624-9. 2004
    ..The kinetic properties of the PDE9A2 catalytic domain similar to those of full-length PDE9A imply that the N-terminal regulatory domain does not significantly alter the catalytic activity and the IBMX inhibition...
  9. pmc Biological and structural characterization of Trypanosoma cruzi phosphodiesterase C and Implications for design of parasite selective inhibitors
    Huanchen Wang
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599 7260, USA
    J Biol Chem 287:11788-97. 2012
    ..The structural study also identified a unique parasite pocket that neighbors the active site and may thus be valuable for the design of parasite-specific inhibitors...
  10. pmc Computer-based redesign of a beta sandwich protein suggests that extensive negative design is not required for de novo beta sheet design
    Xiaozhen Hu
    Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 7260, USA
    Structure 16:1799-805. 2008
    ..However, it is important to note that negative design elements may be encoded in the conformation of the protein backbone which was preserved from the wild-type protein...
  11. pmc Kinetic and structural studies of phosphodiesterase-8A and implication on the inhibitor selectivity
    Huanchen Wang
    Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina 27599 7260, USA
    Biochemistry 47:12760-8. 2008
    ..Thus, the structural and mutagenesis studies provide not only insight into the enzymatic properties but also guidelines for design of PDE8 selective inhibitors...
  12. ncbi request reprint The crystal structure of AMP-bound PDE4 suggests a mechanism for phosphodiesterase catalysis
    Qing Huai
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina 27599 7260, USA
    Biochemistry 42:13220-6. 2003
    ..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...
  13. ncbi request reprint Crystal structures of phosphodiesterases 4 and 5 in complex with inhibitor 3-isobutyl-1-methylxanthine suggest a conformation determinant of inhibitor selectivity
    Qing Huai
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599 7260, USA
    J Biol Chem 279:13095-101. 2004
    ..IBMX binds to a subpocket that comprises key residues Ile-336, Phe-340, Gln-369, and Phe-372 of PDE4D2 or Val-782, Phe-786, Gln-817, and Phe-820 of PDE5A1. This subpocket may be a common site for binding nonselective inhibitors of PDEs...
  14. ncbi request reprint Multiple conformations of phosphodiesterase-5: implications for enzyme function and drug development
    Huanchen Wang
    Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, 27599 7260, USA
    J Biol Chem 281:21469-79. 2006
    ....
  15. pmc Crystal structure of the Leishmania major phosphodiesterase LmjPDEB1 and insight into the design of the parasite-selective inhibitors
    Huanchen Wang
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599 7260, USA
    Mol Microbiol 66:1029-38. 2007
    ..The structure particularity might be useful for the development of parasite-selective inhibitors for the treatment of leishmaniasis...
  16. pmc Conformational variations of both phosphodiesterase-5 and inhibitors provide the structural basis for the physiological effects of vardenafil and sildenafil
    Huanchen Wang
    Department of Biochemistry and Biophysics, The University of North Carolina, Chapel Hill, NC 27599 7260, USA
    Mol Pharmacol 73:104-10. 2008
    ..The conformational variation of both PDE5 and the inhibitors provides structural insight into the different potencies of the drugs...
  17. pmc Refolding and kinetic characterization of the phosphodiesterase-8A catalytic domain
    Zier Yan
    Laboratory of Structure Biology, School of Pharmaceutical Sciences, Sun Yat Sen University, Guangzhou 510275, PR China
    Protein Expr Purif 64:82-8. 2009
    ..Thus, the K(M) difference likely implies an allosteric regulation of the PDE8A activity by its PAS domain...
  18. pmc The molecular basis for different recognition of substrates by phosphodiesterase families 4 and 10
    Huanchen Wang
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599 7260, USA
    J Mol Biol 371:302-7. 2007
    ..These observations imply that individual PDE families have their characteristic mechanisms for substrate recognition...
  19. pmc Crystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes
    Qing Huai
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599 7260, USA
    Proc Natl Acad Sci U S A 99:12037-42. 2002
    ..The comparison of CyPA-CsA-CN with FKBP-FK506-CN significantly contributes to understanding the molecular basis of regulation of CN activity by the immunophilin-immunosuppressant...
  20. pmc Insight into binding of phosphodiesterase-9A selective inhibitors by crystal structures and mutagenesis
    Huanchen Wang
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina 27599 7260, USA
    J Med Chem 53:1726-31. 2010
    ..On the basis of the crystal structures, a hypothesized compound that simulates the recently published PDE9 inhibitors was modeled to provide insight into the inhibitor selectivity...
  21. pmc Enantiomer discrimination illustrated by the high resolution crystal structures of type 4 phosphodiesterase
    Qing Huai
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina 27599 7260, USA
    J Med Chem 49:1867-73. 2006
    ..This model provides explanations for most of the observed structure-activity relationship and the metal ion dependency of the catechol-ether based inhibitors and should facilitate their further design...
  22. pmc Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors
    Huanchen Wang
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599 7260, USA
    Biochem J 408:193-201. 2007
    ..PDE4C appears to be more distal from other PDE4 subfamilies, with certain key residues being disordered. Our analyses provide the first structural basis for the development of PDE4 subfamily-selective inhibitors...
  23. ncbi request reprint Multiple elements jointly determine inhibitor selectivity of cyclic nucleotide phosphodiesterases 4 and 7
    Huanchen Wang
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina 27599 7260, USA
    J Biol Chem 280:30949-55. 2005
    ..The triple S373Y/S377T/I412S mutation of PDE7A1 produces a PDE4-like enzyme, implying that multiple elements must work together to determine inhibitor selectivity...
  24. pmc Conformation changes, N-terminal involvement, and cGMP signal relay in the phosphodiesterase-5 GAF domain
    Huanchen Wang
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599 7260, USA
    J Biol Chem 285:38149-56. 2010
    ..N-terminal loop 98-147 was physically associated with GAF-B domains of the dimer. Biochemical analyses showed an inhibitory effect of this loop on cGMP binding and its involvement in the cGMP-induced conformation changes...
  25. ncbi request reprint Structures of the N-terminal and middle domains of E. coli Hsp90 and conformation changes upon ADP binding
    Qing Huai
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina 27599, USA
    Structure 13:579-90. 2005
    ..Modeling shows that ATP is not exposed to the molecular surface, thus implying that ATP activation of hsp90 chaperone activities is accomplished via conformational changes...
  26. pmc Structure-based discovery of highly selective phosphodiesterase-9A inhibitors and implications for inhibitor design
    Fei Meng
    School of Chemistry and Chemical Engineering, Sun Yat Sen University, Guangzhou 510275, People s Republic of China
    J Med Chem 55:8549-58. 2012
    ..Thus, our studies suggest that Tyr424, a unique residue of PDE8 and PDE9, is a potential target for improvement of selectivity of PDE9 inhibitors...
  27. ncbi request reprint Three-dimensional structures of PDE4D in complex with roliprams and implication on inhibitor selectivity
    Qing Huai
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA
    Structure 11:865-73. 2003
    ..Docking of the PDE5 inhibitor sildenafil into the PDE4 catalytic pocket further helps understand inhibitor selectivity...
  28. ncbi request reprint Crystal structure of DJ-1/RS and implication on familial Parkinson's disease
    Qing Huai
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599 7260, USA
    FEBS Lett 549:171-5. 2003
    ..As a result, the conformational changes may diminish the DJ-1 binding with its partner, leading to the familial Parkinson's disease caused by the single L166P mutation...
  29. pmc Crystallographic and nuclear magnetic resonance evaluation of the impact of peptide binding to the second PDZ domain of protein tyrosine phosphatase 1E
    Jun Zhang
    Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
    Biochemistry 49:9280-91. 2010
    ....
  30. doi request reprint Discovery of 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one as a phosphodiesterase-5 inhibitor and its complex crystal structure
    Na Na Shang
    School of Pharmaceutical Sciences, Sun Yat Sen University, Guangzhou 510006, PR China
    Biochem Pharmacol 89:86-98. 2014
    ..On the basis of the binding pattern of 57, a novel scaffold can be proposed as a candidate of PDE inhibitors...
  31. pmc High-resolution design of a protein loop
    Xiaozhen Hu
    Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA
    Proc Natl Acad Sci U S A 104:17668-73. 2007
    ..These results suggest that the high-resolution design of protein loops is possible; however, they also highlight how small changes in protein energetics can dramatically perturb the low free energy structure of a protein...
  32. ncbi request reprint Crystallization of cyclic nucleotide phosphodiesterases
    Hengming Ke
    Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, USA
    Methods Mol Biol 307:181-90. 2005
    ..Finally, we discuss detailed procedures for and pitfalls of the crystallization of PDEs, which may be valuable for crystallization of other PDE members...
  33. pmc A potential substrate binding conformation of ╬▓-lactams and insight into the broad spectrum of NDM-1 activity
    Qinghui Yuan
    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina, USA
    Antimicrob Agents Chemother 56:5157-63. 2012
    ..Finally, our docking shows that moxalactam uses its tyrosyl-carboxylic group to compete with the S conformer and would thus be a poor substrate of NDM-1...
  34. pmc p53 Oligomerization is essential for its C-terminal lysine acetylation
    Yoko Itahana
    Department of Radiation Oncology, University of North Carolina, Chapel Hill, North Carolina 27599 7512, USA
    J Biol Chem 284:5158-64. 2009
    ..These results, combined with a computer-aided crystal structure analysis, suggest a model in which p53 oligomerization precedes its acetylation by providing docking sites for acetyltransferases...
  35. ncbi request reprint A 46-amino acid segment in phosphodiesterase-5 GAF-B domain provides for high vardenafil potency over sildenafil and tadalafil and is involved in phosphodiesterase-5 dimerization
    Mitsi A Blount
    Department of Molecular Physiology and Biophysics, 702 Light Hall, Vanderbilt University School of Medicine, Nashville, TN 37232 0615, USA
    Mol Pharmacol 70:1822-31. 2006
    ..This is the first evidence that PDE5 R domain, and GAF-B in particular, influences affinity and selectivity of the catalytic site for certain classes of inhibitors...
  36. ncbi request reprint Essential role of the B23/NPM core domain in regulating ARF binding and B23 stability
    Takeharu Enomoto
    Department of Radiation Oncology, University of North Carolina at Chapel Hill, NC 27599 7512, USA
    J Biol Chem 281:18463-72. 2006
    ..B23 core mutants displayed increased ubiquitination and proteasomal degradation. We conclude that the functional integrity of the B23 core motif is required for stability, efficient nucleolar localization as well as ARF binding...
  37. ncbi request reprint Familial Parkinson's disease-associated L166P mutation disrupts DJ-1 protein folding and function
    James A Olzmann
    Departments of Pharmacology, Biochemistry, and Neurology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322 3090, USA
    J Biol Chem 279:8506-15. 2004
    ..Together these findings provide insights into the molecular mechanism by which loss-of-function mutations in DJ-1 lead to Parkinson's disease...
  38. ncbi request reprint Molecular docking of competitive phosphodiesterase inhibitors
    Orly Dym
    University of California Los Angeles Department of Energy Laboratory of Structural Biology and Molecular Medicine, University of California Los Angeles, Los Angeles, California, USA
    Mol Pharmacol 61:20-5. 2002
    ..The binding of other PDE4 inhibitors (high- and low-affinity) was also modeled and used to predict the involvement of residues that were not previously implicated in pharmacological interactions...