Professor, Biological Chemistry
M.Sc., University of Amsterdam, Netherlands
Ph.D., University of Nijmegen (Hilbers), Netherlands
Postdoctoral, University of Groningen (Kaptein), Netherlands
Postdoctoral, ETH Zurich (Wuthrich), Switzerland
NMR studies of Biomacromolecular Conformation, Dynamics and Interactions in Solution
NMR is essential to many biomedical and biomacromolecular research projects for which crystallography is not successful, or too limited in scope. The NMR methodology has now matured to the point that the structure, dynamics and interactions of (complexes of) biomolecules up to 100 kDa can be studied at atomic level. The molecules are in solution and carry out the conformational changes and dynamic interactions necessary for function while the NMR experiments are running.
Our group applies all aspects of these methodologies to study Hsp70 protein-folding chaperone proteins in solution. Hsp70's mediate trafficking, triaging, folding, unfolding and refolding of other proteins in vivo, from bacteria to man. The group's high-resolution solution structure determinations of Hsp70 domains, as well as studies of atom-resolved dynamics and ligand interactions, have led to the formulation of an allosteric mechanism for these proteins. We discover that these active allosteric constructs in solution change their conformation in upon ligand binding, while such is not the case in the crystal. We are also investigating complexes of chaperone and co-chaperone proteins in different allosteric states.
Overexpression Hsp70 proteins contributes to cancer resistance, as well as to tau-protein malfunction in neuronal cells that are affected by Alzheimer’s. With several collaborators, we are using NMR to study the interactions of the Hsp70 proteins with biomolecules involved in these pathologies, as well as with potential Hsp70 inhibitors.
Dynamics (local motion) is an essential component of biological functioning. Without motion, proteins cannot accommodate ligands, carry out chemistry, be allosterically active or be thermally stable. The group is working on the fundamental problem of the modeling of local motions. In several small proteins, the group has found evidence for correlated motions, for conformational change dynamics in enzyme active sites and for large changes in entropy contained in the dynamics of the protein backbone upon ligand binding.
The laboratory uses 600 MHz and 800 MHz NMR spectrometers on campus. The state-of-the-art instruments are equipped with four radio-frequency channels and cryogenic triple-resonance gradient probes for the execution of the most modern multi-dimensional NMR experiments.
1980-1982 Postdoctoral Research Fellowship, Netherlands Organization for the Advancement of Pure Research (ZWO), The Hague, The Netherlands
1982-1983 Postdoctoral Research Fellowship, The Roche Foundation, Basel, Switzerland
1982-1983 Postdoctoral Research Fellowship, The Federation of European Biological Societies
2002 Pfizer Research Award
2004 Fellow of the American Association for the Advancement of Science
Zuiderweg, E.R.P., Hamers, L.F., Rollema, H.S., De Bruin, S.H. and Hilbers, C.W.: 31P NMR study of the kinetics of binding of myo- inositol hexakis phosphate to human hemoglobin; observation of fast-exchange kinetics in in hiGH-affinity systems. Eur. J. Biochem. 118, 95-104 (1981)
Zuiderweg, E.R.P., Kaptein, R. and Wuthrich, K.: Secondary structure of the lac-repressor DNA binding domain by two dimensional 1H NMR in solution. Proc. Natl. Acad. Sci. USA 1983; 80: 5837-5841.
Zuiderweg, E.R.P., Scheek, R.M., Boelens, R., Van Gunsteren, W.F. and Kaptein, R.: Determination of protein structures from nuclear magnetic resonance data using a restrained molecular dynamics approach: the lac-repressor DNA binding domain. Biochimie 1985; 67: 707-715.
Zuiderweg, E.R.P. and Fesik, S.W.: Heteronuclear three-dimensional NMR spectroscopy of the inflammatory protein C5a. Biochemistry, 1989; 28: 2387-2391.
Zuiderweg, E.R.P., Nettesheim, D.G., Mollison, K.W. and Carter, G.W.: Tertiary structure of human complement component C5a in solution from nuclear magnetic resonance data. Biochemistry 28: 172-185 (1989)
Zuiderweg, E.R.P., Petros, A.M., Fesik, S.W. and Olejniczak, E.T. Four-dimensional HMQC-NOESY-HMQC NMR spectroscopy: resolving tertiary distance constraints in the spectra of larger molecules. J. Am. Chem. Soc. 113, 370-372 (1991)
Morshauser, R.C., Wang, H., Flynn, G.C and Zuiderweg, E.R.P. The peptide binding domain of the chaperone-protein Hsc70 has an unusual secondary structure topology. Biochemistry, 1995; 34, 6261-6266
Van Doren, S.W., Kurochkin, A.V., Hu, W., Ye, Q.Z., Johnson, L.L., Hupe, D.J. and Zuiderweg, E.R.P. Solution structure of the catalytic domain of human stromelysin complexed with a hydrophobic inhibitor. Protein Science 4, 2487-2498 (1995)
Wang, H., Pang, Y, Kurochkin, A.V., Hu, W., Flynn, G.C, and Zuiderweg, E.R.P. The solution structure of the 21 kDa chaperone protein DnaK substrate binding domain: a preview of chaperone - protein interaction. Biochemistry 37, 7929-7940 (1998)
Fischer, M.W.F., Zeng, L., Majumdar, A. and Zuiderweg, E.R.P., Characterizing Semi-Local Motions in Proteins by NMR Relaxation Studies, Proc. Natl. Acad. Sci, USA, 95, 8016-8019 (1998)
Morshauser, R.C., Hu, W., Wang, H., Pang, Y., Flynn, G.C. and Zuiderweg, E.R.P. High resolution solution structure of the 18 kda substrate binding domain of the mammalian chaperone protein hsc70. J. Mol. Biol, 289, 1387-1403 (1999)
Pellecchia, M., Stevens, S.Y., Vander Kooi, C.W., Montgomery, D.H., Feng, E.H., Gierasch, L.M., and Zuiderweg, E.R.P. Structural insights into substrate binding by the molecular chaperone DnaK. Nature Structural Biology,7, 298- 303 (2000)
Stevens, S.Y., Sanker, S., Kent, C. and Zuiderweg, E.R.P. Delineation of the allosteric mechanism for a cytidylyltransferase exhibiting negative cooperativity, Nature Structural Biology 8, 947-952 (2001)
Kern, D. and Zuiderweg, E.R.P. The role of dynamics in allosteric regulation, Current Opinion in Structural Biology, 13, 748-757 (2003)
Revington, M., Zhang, Yip, G.N.B., Kurochkin, A.V. and Zuiderweg, E.R.P. NMR investigations of allosteric processes in a two-domain Thermus Thermophilus Hsp70 molecular chaperone, J. Mol. Biol. 349, 163-183 (2005)
Deep, S., Im, S.C., Zuiderweg, E.R.P., and Waskell, L. Characterization and Calculation of a cytochrome c-cytochrome b5 complex using NMR data. Biochemistry 44, 10654-10668 (2005)
Wang, T., Weaver, D.S., Cai, S., Zuiderweg, E.R.P. Quantifying Lipari-Szabo modelfree parameters from 13CO NMR relaxation experiments. J Biomol NMR. 36, 79-102 (2006)
Bhattacharya, A., Kurochkin, A.V., Yip, G.N.B., Zhang, Y., Bertelsen, E.B. and Zuiderweg. E.R.P. Allostery in the Hsp70 chaperones is transduced by subdomain rotations. J. Mol. Biol. 388, 475-490 (2009)
Bertelsen, E.B., Chang, L., Gestwicki, J.E. and Zuiderweg, E.R.P. Solution conformation of E.coli Hsp70 complexed with ADP and substrate. Proc. Natl. Acad. Sci. 106, 8471-8476 (2009)
Rousaki ,A., Miyata, Y., Jinwal, U.K., Dickey, C.A., Gestwicki, J.E., Zuiderweg, E.R.P. Allosteric drugs: the interaction of antitumor compound MKT-077 with human Hsp70 chaperones. J Mol Biol. 411, 614-632 (2011)
Ahmad, A., Bhattacharya, A., McDonald, R.A., Cordes, M., Ellington, B., Bertelsen, E.B., Zuiderweg, E.R.P. Heat shock protein 70 kDa chaperone/DnaJ cochaperone complex employs an unusual dynamic interface. Proc Natl Acad Sci. USA 108, 18966-18971 (2011)
Zuiderweg, E.R.P., Bertelsen, E.B., Rousaki, A., Mayer, M.P., Gestwicki, J.E. and Ahmad, A. Allostery in the Hsp70 chaperone proteins. Topics in Current Chemistry: Molecular Chaperones (Ed. Sophie Jackson), (2012)
Zuiderweg E.R.P., Bagai, I., Rossi, P., Bertelsen, E.B. EZ-ASSIGN, a program for exhaustive NMR chemical shift assignments of large proteins from complete or incomplete triple-resonance data. J Biomol NMR. 57 179-191. (2013)
Smith, M.C, Scaglione, K.M., Assimon V.A., Patury, S., Thompson, A.D., Dickey, C.A., Southworth, D.R., Paulson, H.L., Gestwicki, J.E. and Zuiderweg, E.R.P. The E3 Ubiquitin Ligase CHIP and the Molecular Chaperone Hsc70 Form a Dynamic, Tethered Complex. Biochemistry 52, 5354-5364 (2013)