Faculty / Research

Markus Seeliger, PhD

Assistant Professor 

 

Postdoctoral Fellow with Professor John Kuriyan,UC Berkeley

Ph.D., Cambridge University

Diploma, Biochemistry, Hannover University, Germany

631-444-3558  markus.seeliger@stonybrook.edu
Molecular Mechanism of Protein Kinase and Ubiquitin Ligase signaling in Cancer and Aging

 

Our research group is interested in the molecular mechanism that underlies the signaling of protein tyrosine kinases and ubiquitin ligases. Protein kinases are well established drug targets in oncology and inflammatory diseases. Kinases can access multiple well defined structural states and we are studying how small molecule inhibitors interact with these structures.

 

The aim for this NIH funded project is to understand the conformational exchange between kinase conformations as well as to understand the inhibitory mechanism of kinase inhibitors. For this we are using X-ray crystallography, nulcear magnetic resonance spectroscopy (NMR), protein engineering and other biophysical methods in collaboration with computational biologists. The ubiquitin system relies on a highly modular system of enzymes to ligate ubiquitin onto substrate proteins which in many cases leads to the degradation of the substrate protein via the proteasome. The potential of the ubiquitin system as a therapeutic target is illustrated by the success of the proteasome inhibitor bortezomib in the treatment of multiple myeloma. We are interested in applying concepts from the field of protein kinase research to the study of ubiquitin conjugating enzymes (E2) and ubiquitin ligases (E3) with the aim of enabling specific therapeutics. Our current aim is to study the change in substrate spectra of ubiquitin ligases upon aging in yeast cells. This is work is generously supported by the Ellison Medical Foundation.

Markus Seeliger developed an interest in protein engineering and biophysical chemistry during his diploma research at the Center for Protein Engineering with Alan Fersht and Laura Itzhaki. He pursued his graduate research with Laura Itzhaki on the folding,dynamics and function of a small cell-cycle adapter protein called Cks1.  Incidentally, Cks1 connects kinase and ubiquitin signaling by targeting the Cdk2 inhibitor p27 to the ubiquitin ligase SCF/Skp2. For his postdoctoral research, Markus decided to join John Kuriyan’s group at Berkeley to study the solution dynamics of Abl kinase. This research led into a Pathway to Independence Award from the NIH and in 2009 Markus decided to join the faculty at Stony Brook University Medical School, which provides an exciting environment for biophysical research through proximity to the excellent facilities at Brook Haven National Lab, medical research at Stony Brook Medical School and computational biology at the Laufer Center and to his collaborators in New York.

1. Shan, Y., Kim, E.T., Eastwood, M.P., Dror, R.O., Seeliger, M.A., and Shaw, D.E., How does a drug molecule find its target binding site? J Am Chem Soc, 2011. 133(24): p. 9181-3.

2. Montpetit, B., Thomsen, N.D., Helmke, K.J., Seeliger, M.A., Berger, J.M., and Weis, K., A conserved mechanism of DEAD-box ATPase activation by nucleoporins and InsP6 in mRNA export. Nature, 2011. 472(7342): p. 238-42.

3. Jura, N., Zhang, X., Endres, N.F., Seeliger, M.A., Schindler, T., and Kuriyan, J., Catalytic control in the EGF receptor and its connection to general kinase regulatory mechanisms. Mol Cell, 2011. 42(1): p. 9-22.

4. Weisberg, E., Choi, H.G., Ray, A., Barrett, R., Zhang, J., Sim, T., Zhou, W., Seeliger, M., Cameron, M., Azam, M., Fletcher, J.A., Debiec-Rychter, M., Mayeda, M., Moreno, D., Kung, A.L., Janne, P.A., Khosravi-Far, R., Melo, J.V., Manley, P., Adamia, S., Wu, C., Gray, N., and Griffin, J.D., Discovery of a small molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFR{alpha}, Kit, and Src kinases. Blood, 2010.

5. Shan, Y., Seeliger, M.A., Eastwood, M.P., Frank, F., Xu, H., Jensen, M.O., Dror, R.O., Kuriyan, J., and Shaw, D.E., A conserved protonation-dependent switch controls drug binding in the Abl kinase. Proc Natl Acad Sci U S A, 2009. 106(1): p. 139-44.

6. Seeliger, M.A., Ranjitkar, P., Kasap, C., Shan, Y., Shaw, D.E., Shah, N.P., Kuriyan, J., and Maly, D.J., Equally potent inhibition of c-Src and Abl by compounds that recognize inactive kinase conformations. Cancer Res, 2009. 69(6): p. 2384-92.

7. Seeliger, M.A. and Kuriyan, J., A MAPK scaffold lends a helping hand. Cell, 2009. 136(6): p. 994-6.

8. Muratore, K.E., Seeliger, M.A., Wang, Z., Fomina, D., Neiswinger, J., Havranek, J.J., Baker, D., Kuriyan, J., and Cole, P.A., Comparative analysis of mutant tyrosine kinase chemical rescue. Biochemistry, 2009. 48(15): p. 3378-86.

9. Choi, Y., Seeliger, M.A., Panjarian, S.B., Kim, H., Deng, X., Sim, T., Couch, B., Koleske, A.J., Smithgall, T.E., and Gray, N.S., N-myristoylated c-Abl tyrosine kinase localizes to the endoplasmic reticulum upon binding to an allosteric inhibitor. J Biol Chem, 2009. 284(42): p. 29005-14.

10. Statsuk, A.V., Maly, D.J., Seeliger, M.A., Fabian, M.A., Biggs, W.H., 3rd, Lockhart, D.J., Zarrinkar, P.P., Kuriyan, J., and Shokat, K.M., Tuning a three-component reaction for trapping kinase substrate complexes. J Am Chem Soc, 2008. 130(51): p. 17568-74.

11. Levinson, N.M., Seeliger, M.A., Cole, P.A., and Kuriyan, J., Structural basis for the recognition of c-Src by its inactivator Csk. Cell, 2008. 134(1): p. 124-34.

12. Azam, M., Seeliger, M.A., Gray, N.S., Kuriyan, J., and Daley, G.Q., Activation of tyrosine kinases by mutation of the gatekeeper threonine. Nat Struct Mol Biol, 2008. 15(10): p. 1109-18.

13. Seeliger, M.A., Nagar, B., Frank, F., Cao, X., Henderson, M.N., and Kuriyan, J., c-Src binds to the cancer drug imatinib with an inactive Abl/c-Kit conformation and a distributed thermodynamic penalty. Structure, 2007. 15(3): p. 299-311.

14. Young, M.A., Shah, N.P., Chao, L.H., Seeliger, M., Milanov, Z.V., Biggs, W.H., 3rd, Treiber, D.K., Patel, H.K., Zarrinkar, P.P., Lockhart, D.J., Sawyers, C.L., and Kuriyan, J., Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680. Cancer Res, 2006. 66(2): p. 1007-14.

15. Yao, Z.P., Zhou, M., Kelly, S.E., Seeliger, M.A., Robinson, C.V., and Itzhaki, L.S., Activation of ubiquitin ligase SCF(Skp2) by Cks1: insights from hydrogen exchange mass spectrometry. J Mol Biol, 2006. 363(3): p. 673-86.

16. Nagar, B., Hantschel, O., Seeliger, M., Davies, J.M., Weis, W.I., Superti-Furga, G., and Kuriyan, J., Organization of the SH3-SH2 unit in active and inactive forms of the c-Abl tyrosine kinase. Mol Cell, 2006. 21(6): p. 787-98.

17. Bader, R., Seeliger, M.A., Kelly, S.E., Ilag, L.L., Meersman, F., Limones, A., Luisi, B.F., Dobson, C.M., and Itzhaki, L.S., Folding and fibril formation of the cell cycle protein Cks1. J Biol Chem, 2006. 281(27): p. 18816-24.

18. Seeliger, M.A., Young, M., Henderson, M.N., Pellicena, P., King, D.S., Falick, A.M., and Kuriyan, J., High yield bacterial expression of active c-Abl and c-Src tyrosine kinases. Protein Sci, 2005. 14(12): p. 3135-9.

19. Seeliger, M.A., Spichty, M., Kelly, S.E., Bycroft, M., Freund, S.M., Karplus, M., and Itzhaki, L.S., Role of conformational heterogeneity in domain swapping and adapter function of the Cks proteins. J Biol Chem, 2005. 280(34): p. 30448-59.

20. Mapelli, M., Massimiliano, L., Crovace, C., Seeliger, M.A., Tsai, L.H., Meijer, L., and Musacchio, A., Mechanism of CDK5/p25 binding by CDK inhibitors. J Med Chem, 2005. 48(3): p. 671-9.

21. Seeliger, M.A., Breward, S.E. and Itzhaki, L.S., Weak cooperativity in the core causes a switch in folding mechanism between two proteins of the cks family. J Mol Biol, 2003. 325(1): p. 189-99.

22. Seeliger, M.A., Breward, S.E., Friedler, A., Schon, O., and Itzhaki, L.S., Cooperative organization in a macromolecular complex. Nat Struct Biol, 2003. 10(9): p. 718-24.

23. Sitry, D., Seeliger, M.A., Ko, T.K., Ganoth, D., Breward, S.E., Itzhaki, L.S., Pagano, M., and Hershko, A., Three different binding sites of Cks1 are required for p27-ubiquitin ligation. J Biol Chem, 2002. 277(44): p. 42233-40.

24. Seeliger, M.A., Schymkowitz, J.W., Rousseau, F., Wilkinson, H.R., and Itzhaki, L.S., Folding and association of the human cell cycle regulatory proteins ckshs1 and ckshs2. Biochemistry, 2002. 41(4): p. 1202-10.

We are awaiting the renovation of our new lab space in the Basic Science Tower as well as the Center for Structural Biology.


George Georghiou

Graduate Student in Molecular and Cellular Pharmacology

georghiou@pharm.stonybrook.edu

Benjamin Sondgeroth
Research Support Specialist
Derek Meissner
Postdoctoral Fellow
meissner@pharm.stonybrook.edu
Zack Foda
Graduate Student in Molecular and Cell Biology
Fellow Medical Science Training Program
Michael Pulkoski-Gross
Undergraduate student in Pharmacology