Professor of Biochemistry and Biophysics
(PhD – Harvard University)
X-ray Structures of Phosphodiesterases and Structure-based drug design
Our research focuses on the structure and function of medically important proteins, and structure-based design of inhibitors for treatment of human diseases. The current topics include enzymatic and structural characterization of cyclic nucleotide phosphodiesterases (PDEs), structure-based design of PDE selective inhibitors, and discovery of novel metallo-β-lactamase (MBL) inhibitors to fight against superbugs.
Cyclic nucleotide phosphodiesterase (PDE) hydrolyzes adenosine or guanosine 3′,5′-cyclic phophate (cAMP or cGMP) to 5′-AMP and 5’-GMP. Selective PDE inhibitors towards a certain family of PDEs have been widely studied as therapeutic agents for treatment of various human diseases. An example is the PDE5 inhibitor VIAGRA that is a prescription drug for the treatment of male erectile dysfunction. Our group has solved >30 crystal structures of several PDE families and recently discovered high selective inhibitors of PDE4, PDE5, and PDE9 (Figure 1).
Fig. 1. Binding of a novel inhibitor (green sticks) to the PDE9 active site.
Superbugs are bacteria resistant to most current antibiotics. While the multidrug resistance may be achieved via several mechanisms such as prevention of drug permeation and mutation of drug targeted proteins, identification of a novel enzyme in 2009, called New Delhi metallo-b-lactamase (NDM-1) that decomposes almost all the b-lactam antibiotics and is spreading worldwide, attracts a great attention. To fight the multidrug resistance of pathogens, we are performing structure-based design of NDM-1 inhibitors and obtained some potent inhibitors against NDM-1 and other MBLs.n
- Jansen C, Wang H, Kooistra AJ, de Graaf C, Orrling KM, Tenor H, Seebeck T, Bailey D, de Esch IJ, Ke H, Leurs R. Discovery of novel Trypanosoma brucei phosphodiesterase B1 inhibitors by virtual screening against the unliganded TbrPDEB1 crystal structure. J Med Chem. 2013 Mar 14;56(5):2087-96.
- Meng F, Hou J, Shao YX, Wu PY, Huang M, Zhu X, Cai Y, Li Z, Xu J, Liu P, Luo HB, Wan Y, Ke H. Structure-based discovery of highly selective phosphodiesterase-9A inhibitors and implications for inhibitor design. J Med Chem. 2012 Oct 11;55(19):8549-58.
- Yuan Q, He L, Ke H. A potential substrate binding conformation of b-lactams and insight into the broad spectrum of NDM-1 activity. Antimicrobiol. Agents Chemotherapy, 2012 Jul 23. 56(10):5157-63.
- Wang H, Kunz S, Chen G, Seebeck T, Wan Y, Robinson H, Martinelli S, Ke H. Biological and structural characterization of Trypanosoma cruzi phosphodiesterase C and implications for the design of parasite selective inhibitors. J Biol Chem. 2012 Apr 6;287(15):11788-97.
- Park SJ, Ahmad F, Philp A, Baar K, Williams T, Luo H, Ke H, Rehmann H, Taussig R, Brown AL, Kim MK, Beaven MA, Burgin AB, Manganiello V, Chung JH. (2012) Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell. 148(3):421-33.
- Liu J, Xia H, Kim M, Xu L, Li Y, Zhang L, Cai Y, Norberg HV, Zhang T, Furuya T, Jin M, Zhu Z, Wang H, Yu J, Li Y, Hao Y, Choi A, Ke H, Ma D, Yuan J. (2011) Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell. 2011 Sep 30;147(1):223-34.
- Hou J, Xu J, Liu M, Zhao R, Luo HB, Ke H. (2011) Structural asymmetry of phosphodiesterase-9, potential protonation of a glutamic acid, and role of the invariant glutamine. PLoS One. 2011 Mar 31;6(3):e18092.
- Wang H, Robinson H, Ke H. (2010) Conformation changes, N-terminal involvement, and cGMP signal relay in the phosphodiesterase-5 GAF domain. J Biol Chem. 2010 Dec 3;285(49):38149-56.
- Wang H, Luo X, Ye M, Hou J, Robinson H, Ke H. (2010) Insight into Binding of Phosphodiesterase-9A Selective Inhibitors by Crystal Structures and Mutagenesis. J Med Chem. 2010 Feb 1. 53, 1726-1731.
- Norris RP, Ratzan WJ, Freudzon M, Mehlmann LM, Krall J, Movsesian MA, Wang H, Ke H, Nikolaev VO, Jaffe LA. (2009) Cyclic GMP from the surrounding somatic cells regulates cyclic AMP and meiosis in the mouse oocyte. Development. 2009 Jun;136(11):1869-78.
- Chen G, Wang H, Robinson H, Cai J, Wan Y, Ke H. An insight into the pharmacophores of phosphodiesterase-5 inhibitors from synthetic and crystal structural studies. Biochem Pharmacol. 2008 May 1;75(9):1717-28.
- Wang H, Yan Z, Yang S, Cai J, Robinson H, Ke H. (2008) Kinetic and Structural Studies of Phosphodiesterase-8A and Implication on the Inhibitor Selectivity. Biochemistry. 2008 Dec 2;47(48):12760-12768.
- Hu X, Wang H, Ke H, Kuhlman B. High-resolution design of a protein loop. Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17668-73.
- Wang H, Ye M, Robinson H, Francis SH, Ke H. Conformational variations of both phosphodiesterase-5 and inhibitors provide the structural basis for the physiological effects of vardenafil and sildenafil. Mol Pharmacol. 2008 Jan;73(1):104-10.
- Wang H, Peng MS, Chen Y, Geng J, Robinson H, Houslay MD, Cai J, Ke H. Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors. Biochem J. 2007 Dec 1;408(2):193-201.
- Wang H, Yan Z, Geng J, Kunz S, Seebeck T, Ke H. Crystal structure of the Leishmania major phosphodiesterase LmjPDEB1 and insight into the design of the parasite-selective inhibitors. Mol Microbiol. 2007 Nov;66(4):1029-38.
- Wang H, Robinson H, Ke H. The molecular basis for different recognition of substrates by phosphodiesterase families 4 and 10. J Mol Biol. 2007 Aug 10;371(2):302-7.
- Wang H, Liu Y, Hou J, Zheng M, Robinson H, Ke H. Structural insight into substrate specificity of phosphodiesterase 10. Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5782-7.
- Ke H, Wang H. Crystal structures of phosphodiesterases and implications on substrate specificity and inhibitor selectivity. Curr Top Med Chem. 2007;7(4):391-403. Review.
- Blount MA, Zoraghi R, Ke H, Bessay EP, Corbin JD, Francis SH. 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. Mol Pharmacol. 2006 Nov;70(5):1822-31.
- Wang H, Liu Y, Huai Q, Cai J, Zoraghi R, Francis SH, Corbin JD, Robinson H, Xin Z, Lin G, Ke H. Multiple conformations of phosphodiesterase-5: implications for enzyme function and drug development. J Biol Chem. 2006 Jul 28;281(30):21469-79.
- Enomoto T, Lindström MS, Jin A, Ke H, Zhang Y. Essential role of the B23/NPM core domain in regulating ARF binding and B23 stability. J Biol Chem. 2006 Jul 7;281(27):18463-72.
- Huai Q, Sun Y, Wang H, Macdonald D, Aspiotis R, Robinson H, Huang Z, Ke H. Enantiomer discrimination illustrated by the high resolution crystal structures of type 4 phosphodiesterase. J Med Chem. 2006 Mar 23;49(6):1867-73.
- Wang H, Liu Y, Chen Y, Robinson H, Ke H. Multiple elements jointly determine inhibitor selectivity of cyclic nucleotide phosphodiesterases 4 and 7. J Biol Chem. 2005 Sep 2;280(35):30949-55.
Lab Rooms: 3100D-F Genetic Medicine
Lab Phone: 919-966-7489