个人简介

2013-present Professor, University of Notre Dame 2013-present Associate Dean for Research and Graduate Studies 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 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

研究领域

Biochemistry

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.

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Smitth SN, Wang Y, Baylon JL, Singh NK, Baker BM, Tajkhorshid E, and Kranz DM (2014) Changing the peptide specificity of a human T-cell receptor by directed evolution. Nature Communications Duan F, Duitama J, Al Seesi S, Ayres CM, Corcelli SA, Pawashe AP, Blanchard T, McMahon D, Sidney J, Sette A, Baker BM, Mandoiu II and Srivastava PK (2014). Genomic and bioinformatic profiling of mutational neoepitopes reveals new rules to predict anticancer immunogenicity. Journal of Experimental Medicine Pierce BG, Hellman LM, Hossain M, Singh NK, Vander Kooi CW, Weng Z, and Baker BM (2014). Computational Design of the Affinity and Specificity of a Therapeutic T Cell Receptor. PLoS Computational Biology Hawse WF, De S, Greenwood AI, Nicholson LK, Zajicek J, Kovrigin EL, Kranz DM, Garcia KC, and Baker BM (2014). TCR Scanning of Peptide/MHC through Complementary Matching of Receptor and Ligand Molecular Flexibility. Journal of Immunology Smith SN, Sommermeyer D, Piepenbrink KH, Blevins SJ, Bernhard H, Uckert W, Baker BM, and Kranz D. M. (2013). Plasticity in the Contribution of T Cell Receptor Variable Region Residues to Binding of Peptide–HLA-A2 Complexes. Journal of Molecular Biology Hawse WF, Gloor BE, Ayres CM, Kho K, Nuter E, and Baker BM (2013). Peptide modulation of class I major histocompatibility complex protein molecular flexibility and the implications for immune recognition. Journal of Biological Chemistry Cole DK, Sami M, Scott DR, Rizkallah PJ, Borbulevych OY, Todorov PT, Moysey RK, Jakobsen BK, Boulter JM, Baker BM, and Li Y (2013). Increased peptide contacts govern high affinity binding of a modified TCR whilst maintaining a native pMHC docking mode. Frontiers in Immunology Piepenbrink KH, Blevins SJ, Scott DR, and Baker BM (2013). The basis for limited specificity and MHC restriction in a T cell receptor interface. Nature Communications Madura F, Rizkallah PJ, Miles KM, Holland CJ, Bulek AM, Fuller A, Schauenburg AJ, Miles JJ, Liddy N, Sami M, Li Y, Hossain M, Baker BM, Jakobsen BK, Sewell AK, and Cole DK (2013). T-cell receptor specificity maintained by altered thermodynamics. Journal of Biological Chemistry Scott DR, Vardeman CF, Corcelli SA, and Baker BM (2012). Limitations of time-resolved fluorescence suggested by molecular simulations: assessing the dynamics of T cell receptor binding loops. Biophysical Journal Ekeruche-Makinde J, Clement M, Cole DK, Edwards ES, Ladell K, Miles JJ, Matthews KK, Fuller A, Lloyd KA, Madura F,Dolton GM, Pentier J, Lissina A, Gostick E, Baxter TK, Baker BM, Rizkallah PJ, Price DA, Wooldridge L, Sewell AK (2012). T cell receptor optimized peptide skewing of the T-cell repertoire can enhance antigen targeting. Journal of Biological Chemistry Baker BM, Scott DR, Blevins SJ, and Hawse WF (2012). Structural and dynamic control of T-cell receptor specificity, cross-reactivity, and binding mechanism. Immunological Reviews Hawse WF, Champion MM, Joyce MV, Hellman LM, Hossain M, Ryan V, Pierce BG, Weng Z, and Baker BM (2012) Cutting Edge: Evidence for a dynamically driven T cell signaling mechanism. Journal of Immunology DH Aggen, AS Chervin, TM Schmitt, B Engels, JD Stone, SA Richman, KH Piepenbrink, BM Baker, PD Greenberg, H Schreiber, & DM Kranz (2012). Single-chain VαVβ T-cell receptors function without mispairing with endogenous TCR chains. Gene Therapy M Kumarasiri, LI Llarrull, O Borbulevych, J Fishovitz, E Lastochkin, BM Baker BM, & SM Mobashery (2012). An amino acid position at crossroads of evolution of protein function: antibiotic sensor domain of BlaR1 protein from Staphylococcus aureus versus class D β-lactamases. Journal of Biological Chemistry Scott DR, Borbulevych OY, Piepenbrink KH, Corcelli SA, & Baker BM (2011). Disparate degrees of hypervariable loop flexibility control T-cell receptor cross-reactivity, specificity, and binding mechanism. Journal of Molecular Biology Insaidoo FK, Borbulevych OY, Hossain M, Santhanagopolan SM, Baxter TK, & Baker BM (2011). Loss of T cell antigen recognition arising from changes in peptide and major histocompatibility complex protein flexibility: implications for vaccine design. Journal of Biological Chemistry Borbulevych O, Kumarasiri M, Wilson B, Llarrull LI, Lee M, Hesek D, Shi Q, Peng P, Baker BM, & Mobashery SM (2011). Lysine NZ-decarboxylation switch and activation of the b-lactam sensor domain of BlaR1 protein of methicillin-resistant Staphylococcus aureus. Journal of Biological Chemistry Borbulevych OY, Santhanagopolan SM, Hossain M, & Baker BM (2011). TCRs used in cancer gene therapy cross-react with MART-1/Melan-A tumor antigens via distinct mechanisms. Journal of Immunology Aggen DH, Chervin AS, Insaidoo FK, Piepenbrink KH, Baker BM, & Kranz DM (2011). Identification and engineering of human variable regions that allow expression of stable single-chain T cell receptors. Protein Engineering, Design and Selection