department of pharmacology

Matthias Buck, Ph.D.



Case Western Reserve University
School of Medicine
Department of Physiology & Biophysics
Cleveland, Ohio 44106-4970

Phone: (216) 368-8651
Fax: (216) 368-1693


The structure and dynamics of proteins determines the mechanisms by which signals are transmitted in cells. Our laboratory especially characterizes the structures and the dynamics of proteins involved in protein-protein interactions. Understanding the molecular determinants that are responsible for signal transduction is important as this knowledge will allow us to gain insight into how the normal function of signaling proteins is disrupted by mutations in diseased states. Knowing at near-atomic resolution which residues interact in protein complex formation will allow us to rationalize their interaction affinity and specificity. Furthermore, it will provide an opportunity for us to alter the proteins for diagnostic or therapeutic purposes. Fundamentally, we will gain a deep insight into how proteins are used for signaling in the specific systems.

Specific Projects

  1. Structure and Signaling Functions of the Plexin Transmembrane Receptor. This protein receives guidance cues (such as Semaphorins and Neuropilins) and is activated by them. Such cues allow the cells to decide whether to move towards another cell, or away from it. This process of guidance is in part responsible for "wiring up" the nervous and the vascular system. The same family of receptors is also important in immunology and cancer (binding to the Met receptor tyrosine kinase). The plexin protein is unique, as it is the first example of a receptor that interacts directly with small GTPases. We have recently determined the NMR solution structure of the Rac1 binding domain of plexin-B1 and are now refining the structure of several complexes. Using the structural information, we are altering the binding affinity and specificity of this domain towards various GTPases.
  2. Role of Phosphorylation in small GTPase Signaling. Using an in vitro protein biophysics approach we are characterizing phosphorylation patterns in regulatory and effector proteins that result from their exposure to a variety of active Ser/Thr as well as Tyr kinases. Biochemical assays put a limit on the effects that are observed on the protein’s function as a consequence of the phosphorylation. The relevant sites are then mutated (mimicking the dominant negative and constitutively active forms) and the role of the phosphorylation is then verified in vivo.
  3. Structure and Signaling Functions of the Eph-A1 and -B1 Transmembrane Receptors. Eph receptors comprise a highly abundant family of receptor tyrosine kinases, also involved in cell guidance, attachment and proliferation. Although the structures of several of the cytoplasmic domains have been determined, the overall protein conformational changes that take place in signaling are not understood.

Techniques used in the Laboratory include Molecular Biology, Protein Biochemistry, Structural and Thermodynamics measurements by Circular Dichroism and Fluorescence Spectroscopy, as well as Isothermal Titration Calorimetry and Amide Hydrogen Exchange. The principle tool we use to look at protein structures, their dynamics and interactions is solution NMR Spectroscopy and recently X-ray Crystallography but we also make comparisons with Molecular Dynamics Computer Simulations and Modeling.


Buck, M. & Rosen, M.K. (2001) "Flipping a switch". Perspective in Science 291, 2329-2330.

Pang, Y., Buck, M., & Zuiderweg, R.P. (2002) "Backbone dynamics of the Ribonuclease Binase using multinuclear (15N and 13CO) NMR Relaxation and Computational Molecular Dynamics " Biochemistry 41, 2655-2666.

Buck, M. (2003) "Crystallography: Embracing Conformational Flexibility in Proteins." Structure (Cambridge) 11, 735-736.

Buck, M., Xu, W. & Rosen, M.K*. (2004) "A two state allosteric model for autoinhibition in WASP" J.Mol.Biol. 338, 271-285; cover article

Tong, Y., Hughes, D., Placanica, L. & Buck, M (2005) "When monomers are
preferred: A strategy for the identification and disruption of weakly oligomerized proteins " Structure (Cambridge) 13, 5-17.

Tong, Y., & Buck, M (2005) "1H, 15N, 13C assignments and secondary structure characterization reveal that the Rac1 binding domain of plexin-B1 has an ubiqiutin fold" J.BioMol.NMR 31, 369-370.

Li, X., Hümmer, A., Han, J., Xie, Y., Melnik-Martinez, K., Moreno, R.L., Buck, M., Mark, M.D., & Herlitze, S.G. (2005) "Protein beta 2 subunit derived peptides for inhibition and induction of G protein pathways:
Examination on voltage gated Ca2+ and G protein inward rectifying K+ channels". J.Biol.Chem. 280, 23945-23959.

Buck, M, Bouguet-Bonnet, S., Pastor, R.W., & MacKerell, A.D. (2005) "Importance of the CMAP correction to the CHARMM22 protein force field:
Dynamics of Hen Lysozyme" Biophys.J. 90, L36-9.

Bouguet-Bonnet, S. & Buck, M (2006) "1H, 15N, 13C assignments for the activated forms of the small Rho-GTPase Rac1" in press J. BioMol.NMR