Department of Chemistry & Biochemistry

Biography

2016-present

Rev. John A. Zahm Professor of Structural Biology, University of Notre Dame

2016-present

Chair, Department of Chemistry & Biochemistry, 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

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 researchers 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 histocomatibility 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 Papers

• Spear, T.T., Wang, Y., Smith, T.W., Jr., Simms, P.E., Garrett-Mayer, E., Hellman, L.M., Baker, B.M., Nishimura, M.I. "Altered Peptide Ligands Impact the Diversity of Polyfunctional Phenotypes in T Cell Receptor Gene-Modified T Cells" 2018 Molecular Therapy, 26 (4), pp. 996-1007. DOI: 10.1016/j.ymthe.2018.01.015
• Moore, T., Wagner, C.R., Scurti, G.M., Hutchens, K.A., Godellas, C., Clark, A.L., Kolawole, E.M., Hellman, L.M., Singh, N.K., Huyke, F.A., Wang, S.-Y., Calabrese, K.M., Embree, H.D., Orentas, R., Shirai, K., Dellacecca, E., Garrett-Mayer, E., Li, M., Eby, J.M., Stiff, P.J., Evavold, B.D., Baker, B.M., Le Poole, I.C., Dropulic, B., Clark, J.I., Nishimura, M.I. "Clinical and immunologic evaluation of three metastatic melanoma patients treated with autologous melanoma-reactive TCR-transduced T cells" 2018 Cancer Immunology, Immunotherapy, 67 (2), pp. 311-325. DOI: 10.1007/s00262-017-2073-0
• Eby, J.M., Smith, A.R., Riley, T.P., Cosgrove, C., Ankney, C.M., Henning, S.W., Paulos, C.M., Garrett-Mayer, E., Luiten, R.M., Nishimura, M.I., Baker, B.M., Le Poole, I.C. "Molecular properties of gp100-reactive T-cell receptors drive the cytokine profile and antitumor efficacy of transgenic host T cells" 2018 Pigment Cell and Melanoma Research, Article in Press. DOI: 10.1111/pcmr.12724
• Spear, T.T., Wang, Y., Foley, K.C., Murray, D.C., Scurti, G.M., Simms, P.E., Garrett-Mayer, E., Hellman, L.M., Baker, B.M., Nishimura, M.I. "Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells" 2017 Cancer Immunology, Immunotherapy, 66 (11), pp. 1411-1424. DOI: 10.1007/s00262-017-2032-9
• Singh, N.K., Riley, T.P., Baker, S.C.B., Borrman, T., Weng, Z., Baker, B.M. "Emerging concepts in TCR specificity: Rationalizing and (Maybe) predicting outcomes" 2017 Journal of Immunology, 199 (7), pp. 2203-2213. DOI: 10.4049/jimmunol.1700744
• Wang, Y., Singh, N.K., Spear, T.T., Hellman, L.M., Piepenbrink, K.H., McMahan, R.H., Rosen, H.R., Vander Kooi, C.W., Nishimura, M.I., Baker, B.M. "How an alloreactive T-cell receptor achieves peptide and MHC specificity" 2017 Proceedings of the National Academy of Sciences of the United States of America, 114 (24), pp. E4792-E4801. DOI: 10.1073/pnas.1700459114

>> See our full list of publications at PubMed >>

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