Brian M. Baker // People // Department of Chemistry & Biochemistry // University of Notre Dame

Brian M. Baker

Biophysics and Structural Biology of molecular recognition and cellular communication

Biography

2021-present: Coleman Professor of Life Sciences, University of Notre Dame
2016-present: Chair, Department of Chemistry & Biochemistry, University of Notre Dame
2016-2021: Rev. John A. Zahm Professor of Structural Biology, University of Notre Dame
2013-2016: Professor, University of Notre Dame
2013-2016: Associate Dean for Research and Graduate Studies
2011-2013: Founding Director, Integrated Biomedical Sciences Graduate Program, University of Notre Dame
2008-2012: Director of Graduate Studies, Department of Chemistry & Biochemistry, University of Notre Dame
2007-2013: Associate Professor, University of Notre Dame
2001-2007: Assistant Professor, University of Notre Dame
1998-2001: Postdoctoral Fellow, Harvard University
1997: Ph.D. in Biochemistry, University of Iowa
1992: B.S. in Biochemistry, New Mexico State University

Selected Awards

2018: Coaches vs. Cancer Innovator Award
2014: Rev. Edmund P. Joyce, C.S.C. Award for Excellence in Undergraduate Teaching
2012: Director of Graduate Studies Award
2005: Research Scholar of the American Cancer Society
2005: NSF Career Award
1998-2001: Cancer Research Institute Postdoctoral Fellowship

Research Interests

How do biological molecules specifically recognize targets, how does recognition lead to cellular communication, and how do the physical aspects of these processes give rise to biological function? The Baker laboratory researches these broad areas utilizing a diverse array of structural, biophysical, biochemical, and biological approaches. Our work emphasizes molecular recognition, communication, and function in the general areas of cellular immunity and bacterial antibiotic resistance. Techniques used in the lab include solution biophysics, protein crystallography and NMR, mass spectrometry, computational biochemistry, and biological experiments with mammalian cell cultures. Ongoing projects include:

The basis for antigen recognition in cellular immunity: The goal of this project is to understand how T cells of the immune system are able to specifically recognize some antigenic ligands, yet avoid others. We focus on the T cell receptor and its ligand, small peptides bound and "presented" by major histocompatibility complex proteins, asking how structures, flexibilities, and chemical features give rise to recognition behavior. Beyond helping us understand the basic biochemistry of molecular recognition, our studies have implications for the functioning of the immune system, the immune response to cancer and infectious disease, and autoimmunity.

The physical basis for T cell signaling: The T cell receptor complex on the surface of a T cell is a large, multi-protein supramolecular assembly. Here we aim to understand how this assembly is able to communicate the presence of a ligand to the interior of a cell. Utilizing basic principles of allosteric communication, we are exploring the idea that alterations in flexibility give rise to architectural changes on the outside of the cell that alter the positions of signaling modules on the inside of the cell. An important goal of this project is to determine the three-dimensional structure of the complex on the surface of a living cell, which will ultimately allow us to directly relate structural and physical properties to biology.

Design of novel immunologically-based therapeutics: In partnership with computational biologists and immunologists, we are engineering immune receptors to target antigens presented by cancer cells with high affinity, working towards enhancing the immune response to cancer. In the context of this work, we are generating mice with genetically engineered immune systems that specifically target cancer. In a related project, we are working with medicinal chemists to design new vaccine candidates based on cellular immunity.

The physical mechanisms underlying bacterial antibiotic sensors: The evolution of bacterial antibiotic resistance is a significant threat to public health. Bacteria sense the presence of antibiotics via a "sensor" protein on the cell surface. Recognition of an antibiotic is communicated into the cell, leading to upregulation of the resistance machinery. We are studying how these sensor proteins evolved from machinery utilized in cell wall biosynthesis and how small structural differences give rise to significant changes in biological function. Taking cues from our work in the immune system, we are asking how recognition of an antibiotic by the sensor is communicated from the outside of the cell to the inside, with the long term goal of disrupting this process for the development of novel classes of antibiotics.

Recent Publications

Brennick, C. A., George, M. M., Moussa, M. M., Hagymasi, A. T., Seesi, S. A., Shcheglova, T. V., Englander, R. P., Keller, G. L. J., Balsbaugh, J. L., Baker, B. M., Schietinger, A., Mandoiu, I. I., Srivastava, P. K. "An unbiased approach to defining bona fide cancer neoepitopes that elicit immune-mediated cancer rejection" 2021 Journal of Clinical Investigation, 131 (3), e142823. DOI:10.1172/JCI142823.
McGrath, E., Waschbüsch, D., Baker, B. M., Khan, A. R. "LRRK2 binds to the Rab32 subfamily in a GTP-dependent manner via its armadillo domain" 2021 Small GTPases, 12 (2), pp. 133-146. DOI:10.1080/21541248.2019.1666623.
Schmidt, J., Smith, A. R., Magnin, M., Racle, J., Devlin, J. R., Bobisse, S., Cesbron, J., Bonnet, V., Carmona, S. J., Huber, F., Ciriello, G., Speiser, D. E., Bassani-Sternberg, M., Coukos, G., Baker, B. M., Harari, A., Gfeller, D. "Prediction of neo-epitope immunogenicity reveals TCR recognition determinants and provides insight into immunoediting" 2021 Cell Reports Medicine, 2 (2), 100194. DOI:10.1016/j.xcrm.2021.100194.
Smith, A. R., Alonso, J. A., Ayres, C. M., Singh, N. K., Hellman, L. M., Baker, B. M. "Structurally silent peptide anchor modifications allosterically modulate T cell recognition in a receptor-dependent manner" 2021 Proceedings of the National Academy of Sciences of the United States of America, 118 (4), e2018125118. DOI:10.1073/pnas.2018125118.
Singh, N. K., Alonso, J. A., Harris, D. T., Anderson, S. D., Ma, J., Hellman, L. M., Rosenberg, A. M., Kolawole, E. M., Evavold, B. D., Kranz, D. M., Baker, B. M. "An engineered T cell receptor variant realizes the limits of functional binding modes" 2020 Biochemistry, 59 (43), pp. 4163-4175. DOI:10.1021/acs.biochem.0c00689.
Devlin, J. R., Alonso, J. A., Ayres, C. M., Keller, G. L. J., Bobisse, S., Vander Kooi, C. W., Coukos, G., Gfeller, D., Harari, A., Baker, B. M. "Structural dissimilarity from self drives neoepitope escape from immune tolerance" 2020 Nature Chemical Biology, 16 (11), pp. 1269-1276. DOI:10.1038/s41589-020-0610-1.