Zhang Initiative Research Unit

Initiative Research Scientist

Kam Y. J. Zhang

  • Ph.D.
  • Kam Y. J. Zhang
  • Brief resume
    1989
    Ph.D., University of York, UK
    1989
    Postdoctoral Research Fellow, University of California, Los Angeles, USA
    1994
    Assistant Member, Fred Hutchinson Cancer Research Center, USA
    1995
    Affiliate Assistant Professor, University of Washington, USA.
    2001
    Group Leader, Structural Biology, Structural Genomics Inc., USA
    2002
    Director of Structural Biology, Plexxikon Inc., USA
    2009
    Initiative Research Scientist, Zhang Initiative Research Unit, RIKEN (-current)
    2010
    Affiliate Associate Professor, Department of Computational Biology, Graduate School of Frontier Science, University of Tokyo (-current)

Outline

Zhang Initiative Research Unit

We seek to exploit methodologies developed for protein folding prediction and utilize them to solve the X-ray crystallographic phase problem. The solution to the protein-folding problem has been hindered by the lack of a precise energy function and prohibitive computational costs in searching for the global energy minimum conformation. We separate the energy function from the conformational search by providing X-ray diffraction data as a pseudo energy function to solve the folding problem. We develop efficient search methods and utilize advanced computational techniques to tackle the astronomical conformational search problem. This would also solve the phase problem, since the predicted structure provides constraints upon which the phases can be retrieved.

Recent Research Topic

Combining constraints to solve the crystallographic phase problem

In X-ray crystallography, the amplitudes of the diffracted X-ray waves can be measured but not their phases. The missing phase information can be retrieved by applying physico-chemical constraints
Fig. 1
In X-ray crystallography, the amplitudes of the diffracted X-ray waves can be measured but not their phases. The missing phase information can be retrieved by applying physico-chemical constraints.

We have developed a new method of protein phase improvement using the joint distribution of the electron density and its gradient as a constraint in a density-modification procedure. This has been incorporated into the program suite, SQUASH. This and its successor, DM, have been widely used in the X-ray crystallographic community. We have combined the constraints of correct electron-density distribution, solvent flatness, correct local shape of the electron density and equal molecules in an integrated procedure for macromolecular phase improvement. These constraints on electron densities are satisfied simultaneously by solving a system of non-linear equations.

Selected Publications

  1. F. Berenger, R. Shrestha, Y. Zhou, D. Simoncini, K. Y. J. Zhang, Durandal: fast exact clustering of protein decoys, J. Comp. Chem. 2012, 33, 471.
  2. A. Kumar, K. Y. J. Zhang, Computational Fragment-based Screening Using RosettaLigand: the SAMPL3 Challenge, J. Comput. Aided Mol. Des. 2012, doi: 10.1007/s10822-011- 9523-0.
  3. R. Shrestha, F. Berenger, K. Y. J. Zhang, Accelerating ab initio phasing with de novo models, Acta Cryst. 2011, D67, 804.
  4. F. Berenger, Y. Zhou, R. Shrestha, K. Y. J. Zhang, Entropy-accelerated exact clustering of protein decoys, Bioinformatics 2011, 27, 939.
  5. G. Bollag, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma, Nature 2010, 467, 596.
  6. F. Berenger, C. Coti, K. Y. J. Zhang, PAR: a PARallel and distributed job crusher, Bioinformatics 2010, 26, 2918.
  7. D. R. Artis, et al. Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent, Proc. Natl Acad. Sci. USA 2009, 106, 262.
  8. J. Tsai, et al. Discovery of a Novel Selective Inhibitor of Oncogenic B-Raf Kinase with Potent Anti-Melanoma Activity, Proc. Natl Acad. Sci. USA 2008, 105, 3041.
  9. K. Y. J. Zhang, et al. Scaffold-based drug discovery, Chapter 6 in Structure-based Drug Discovery, 2007, 129, Eds. Harren Jhoti and Andrew Leach, Springer, Dordrecht/Boston/London.
  10. K. Y. J. Zhang, Crystal structure of PDE families and the potential for rational drug design, Chapter 29 in Cyclic Nucleotide Phosphodiesterases in Health and Disease, 2006, 583, Eds. Joseph A. Beavo, Sharron H. Francis and Miles D. Houslay, CRC Press, Boca Raton/London/New York.
  11. Houslay, M. D., et al. Keynote review: Phosphodiesterase-4 as a therapeutic target. Drug Discovery Today 2005, 10, 1503.
  12. G. L. Card, et al. A family of phosphodiesterase inhibitors discovered by cocrystallography and scaffold-based drug design, Nature Biotechnol. 2005, 23, 201.
  13. K. Y. J. Zhang, et al. A Glutamine Switch Mechanism for Nucleotide Selectivity by Phosphodiesterases, Molecular Cell 2004, 15, 279.

Core Members

Principal Investigator add delete
Kam Zhang Initiative Research Scientist    
Staff Scientist add delete
Postdoctoral Fellow add delete
Kamlesh Kumar Sahu Postdoctoral Researcher    
Ashutosh Kumar Postdoctoral Researcher    
Taeho Jo Postdoctoral Researcher    
David Simoncini Postdoctoral Researcher    
Muhammad Muddassar Postdoctoral Researcher    
Arnout Richard Dominiek Voet Postdoctoral Researcher    
Student Trainee add delete
Rojan Shrestha International Program Associate    
Technical Assistant add delete
Francois Charles Matthieu Berenger Technical Staff I    
Administrative Assistant add delete
Visiting Research Staff add delete
Other Staff add delete
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