@article{93340f2e68b14d5984fb33c9e969eb4f,
title = "An engineered T cell receptor variant realizes the limits of functional binding modes",
abstract = "T cell receptors (TCRs) orchestrate cellular immunity by recognizing peptides presented by a range of major histocompatibility complex (MHC) proteins. Naturally occurring TCRs bind the composite peptide/MHC surface, recognizing peptides that are structurally and chemically compatible with the TCR binding site. Here we describe a molecularly evolved TCR variant that binds the human class I MHC protein HLA-A2 independent of the bound peptide, achieved by a drastic perturbation of the TCR binding geometry that places the molecule far from the peptide binding groove. This unique geometry is unsupportive of normal T cell signaling. A substantial divergence between affinity measurements in solution and in two dimensions between proximal cell membranes leads us to attribute the lack of signaling to steric hindrance that limits binding in the confines of a cell-cell interface. Our results provide an example of how receptor binding geometry can impact T cell function and provide further support for the view that germline-encoded residues in TCR binding loops evolved to drive productive TCR recognition and signaling.",
author = "Singh, {Nishant K.} and Alonso, {Jesus A.} and Harris, {Daniel T.} and Anderson, {Scott D.} and Jiaqi Ma and Hellman, {Lance M.} and Rosenberg, {Aaron M.} and Kolawole, {Elizabeth M.} and Evavold, {Brian D.} and Kranz, {David M.} and Baker, {Brian M.}",
note = "Supported by Grants R35GM118166 from the National Institute of General Medical Sciences to B.M.B., R01CA178844 from the National Cancer Institute to D.M.K., and R01AI147641 from the National Institute of Allergy and Infectious Diseases to B.D.E. J.A.A. and A.M.R. were supported by Grants TL1TR001107 and TL1TR002531, respectively, from the National Center for Advancing Translational Sciences. D.T.H. was supported by Grant F30CA180723 from the National Cancer Institute. X-ray diffraction data were collected at SER-CAT, supported by its member institutions and Grants S10RR25528 and S10RR028976 from the National Institutes of Health. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract W-31-109-Eng-38. Supported by Grants R35GM118166 from the National Institute of General Medical Sciences to B.M.B., R01CA178844 from the National Cancer Institute to D.M.K., and R01AI147641 from the National Institute of Allergy and Infectious Diseases to B.D.E. J.A.A. and A.M.R. were supported by Grants TL1TR001107 and TL1TR002531, respectively, from the National Center for Advancing Translational Sciences. D.T.H. was supported by Grant F30CA180723 from the National Cancer Institute. X-ray diffraction data were collected at SER-CAT, supported by its member institutions and Grants S10RR25528 and S10RR028976 from the National Institutes of Health. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract W-31-109-Eng-38.",
year = "2020",
month = nov,
day = "3",
doi = "10.1021/acs.biochem.0c00689",
language = "English (US)",
volume = "59",
pages = "4163--4175",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "43",
}