Rev. John A. Zahm Professor of Chemistry & Biochemistry; Department Chair, Chemistry & Biochemistry
Research in the Baker lab is directed at understanding and manipulating molecular recognition in the cellular immune system using fundamental biophysical principles. We are primarily interested in antigen presentation by major histocompatibility complex molecules, their recognition by T cell receptors, and the design and engineering of novel cancer therapeutics based on T cell-mediated immunity. Our approach integrates structural biology, protein biophysics, and molecular immunology.
Most cells in the body express class I or class II major histocompatibility complex proteins (MHC), or MHC proteins, which bind and “present” peptides derived from intracellular or extracellular proteins. Recognition of a peptide/MHC complex by a T cell receptor (TCR) on the surface of a helper or cytotoxic T cell stimulates a T cell-mediated immune response. While best recognized for its role in the immune response to viruses, T cell mediated immunity also plays a key role in the immune response to other pathogens, in transplant rejection, autoimmunity, and cancer.
Many projects in the lab are centered on the structural and biophysical principles of TCR recognition of peptide/MHC. The TCR-pMHC interaction is one of the most complex protein-ligand interactions known to biology. We aim to understand the complexities from a physical perspective, using techniques such as protein crystallography, NMR, mass spectrometry, and experimental and computational biophysics.
As we gain insight into TCR recognition of peptide/MHC, we are using this knowledge to engineer TCRs with improved recognition properties with the goal of developing novel therapeutics. Here we rely heavily on computational protein design methods. Other projects are centered on understanding how recognition is communicated across the cell membrane. In this work we aim to gain a deeper understanding of the molecular changes that occur upon binding and how these influence protein architecture and connections with cell signaling units.
Lastly, we have a special interest in the immune response to cancer. There is a close connection between cellular immunity and cancer, and some of the earliest cancer treatments of the modern era focused on eliciting or enhancing anti-cancer immune responses. We study the development and enhancement of cancer vaccines as well as sophisticated approaches that involve the creation of genetically engineered immune systems for cancer patients. In these areas, we leverage our understanding of the biophysical underpinnings of TCR recognition of peptide/MHC in order to help drive advances in cancer immunology.
- "How an alloreactive T-cell receptor achieves peptide and MHC specificity” 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. P. Natl. Acad. Sci. USA 2017, 114(24), E4792-E480.
- “A generalized framework for computational design and mutational scanning of T-cell receptor binding interfaces” Riley, T.P.; Ayres, C.M.; Hellman, L.M.; Singh, N.K.; Cosiano, M.; Cimons, J.M.; Anderson, M.J.; Piepenbrink, K.H.; Pierce, B.G.; Weng, Z.; Baker, B.M. Protein Eng. Des. Sel. 2016, 29(12), 595-606.
- “An Engineered Switch in T Cell Receptor Specificity Leads to an Unusual but Functional Binding Geometry” Harris, D.T.; Singh, N.K.; Cai, Q.; Smith, S.N.; Vander Kooi, C.W.; Procko, E.; Kranz, D.M.; Baker, B.M. Structure 2016, 24(7), 1142-1154.
- "How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire." Blevins, S.J.; Pierce, B.G.; Singh, N.K.; Riley, T.P.; Wang, Y.; Spear, T.T.; Nishimura, M.I.; Weng, Z.; Baker, B.M. P. Natl. Acad. Sci. USA 2016, 113(9), E1276-E1285.