Hengming Ke, PhD

HONORS & AWARDS

RESEARCH

Summary:

X-ray Protein Crystallography and Structures of Cyclophilin, Calcineurin, HIV Gag Protein

Our research focuses on the structure and function of medically important proteins from the crystallographic approach. The current topics include cyclophilin, calcineurin, heat shock protein 90 (Hsp90), and cyclic nucleotide phosphodiesterase.

Cyclophilin (CyP) is a binding protein for the immunosuppressive drug cyclosporin A (CsA) and also an Ke graphicenzyme catalyzing the cis-trans isomerization of a peptidyl-prolyl bond. The CyP-CsA complex binds calcineurin, a calmodulin-dependent serine/threonine protein phosphatase in signal transduction pathway towards T-cell activation. Cyclophilin has been reported to be involved in protein folding and to function as a molecular chaperone in biological systems. Cyclophilin 40 is a member of the Hsp90 molecular chaperone system that regulates many biological processes such as the steroid hormone signaling pathway. In addition, cyclophilin binds the HIV-1 capsid protein and is required for HIV-1 infectivity. Our crystal structures of CyP, CyP in complex with CsA and the HIV peptide, and the CyP-calcineurin complex have provided insight into the mechanism of the cis-trans isomerization, the regulation of HIV-1 activity by CyP, and the signal transduction towards T-cell activation.

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 such as cardiotonic agents, vasodilators, smooth muscle relaxants, antiasthma, antithrombotic compounds, and antidepressants. For example, the PDE5 inhibitor VIAGRA is a prescription drug for erectile dysfunction of male patients. Our structural studies on PDE4B and PDE4D have provided insight into the substrate specificity and inhibitor selectivity of the PDE families, and a guideline for development of new drugs for various human diseases.

REPRESENTATIVE PUBLICATIONS

      • 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.
      • 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.
      • Ke H, Huai Q, Xu RX. Crystallization of cyclic nucleotide phosphodiesterases. Methods Mol Biol. 2005;307:181-90.
      • Huai Q, Wang H, Liu Y, Kim HY, Toft D, Ke H. Structures of the N-terminal and middle domains of E. coli Hsp90 and conformation changes upon ADP binding. Structure. 2005 Apr;13(4):579-90.

          CONTACT INFO

          3077 Genetic Medicine Bldg
          Campus Box 7260
          Chapel Hill, NC 27599

          Office: 919-966-2244
          Fax: 919-966-2852

          hke@med.unc.edu

          Ke Lab Website