Karsten Dean Householder
Ph.D. Student in Immunology, admitted Autumn 2023
Contact
https://orcid.org/0000-0003-0282-4479All Publications
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De novo design and structure of a peptide-centric TCR mimic binding module.
bioRxiv : the preprint server for biology
2024
Abstract
T cell receptor (TCR) mimics offer a promising platform for tumor-specific targeting of peptide-MHC in cancer immunotherapy. Here, we designed a de novo α-helical TCR mimic (TCRm) specific for the NY-ESO-1 peptide presented by HLA-A*02, achieving high on-target specificity with nanomolar affinity (Kd = 9.5 nM). The structure of the TCRm/pMHC complex at 2.05 Å resolution revealed a rigid TCR-like docking mode with an unusual degree of focus on the up-facing NY-ESO-1 side chains, suggesting the potential for reduced off-target reactivity. Indeed, a structure-informed in silico screen of 14,363 HLA-A*02 peptides correctly predicted two off-target peptides, yet our TCRm maintained a wide therapeutic window as a T cell engager. These results represent a path for precision targeting of tumor antigens with peptide-focused α-helical TCR mimics.
View details for DOI 10.1101/2024.12.16.628822
View details for PubMedID 39763827
View details for PubMedCentralID PMC11702606
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Structure of the interleukin-5 receptor complex exemplifies the organizing principle of common beta cytokine signaling.
Molecular cell
2024
Abstract
Cytokines regulate immune responses by binding to cell surface receptors, including the common subunit beta (βc), which mediates signaling for GM-CSF, IL-3, and IL-5. Despite known roles in inflammation, the structural basis of IL-5 receptor activation remains unclear. We present the cryo-EM structure of the human IL-5 ternary receptor complex, revealing architectural principles for IL-5, GM-CSF, and IL-3. In mammalian cell culture, single-molecule imaging confirms hexameric IL-5 complex formation on cell surfaces. Engineered chimeric receptors show that IL-5 signaling, as well as IL-3 and GM-CSF, can occur through receptor heterodimerization, obviating the need for higher-order assemblies of βc dimers. These findings provide insights into IL-5 and βc receptor family signaling mechanisms, aiding in the development of therapies for diseases involving deranged βc signaling.
View details for DOI 10.1016/j.molcel.2024.03.023
View details for PubMedID 38614096
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Structural insights into the mechanism of leptin receptor activation.
Nature communications
2023; 14 (1): 1797
Abstract
Leptin is an adipocyte-derived protein hormone that promotes satiety and energy homeostasis by activating the leptin receptor (LepR)-STAT3 signaling axis in a subset of hypothalamic neurons. Leptin signaling is dysregulated in obesity, however, where appetite remains elevated despite high levels of circulating leptin. To gain insight into the mechanism of leptin receptor activation, here we determine the structure of a stabilized leptin-bound LepR signaling complex using single particle cryo-EM. The structure reveals an asymmetric architecture in which a single leptin induces LepR dimerization via two distinct receptor-binding sites. Analysis of the leptin-LepR binding interfaces reveals the molecular basis for human obesity-associated mutations. Structure-based design of leptin variants that destabilize the asymmetric LepR dimer yield both partial and biased agonists that partially suppress STAT3 activation in the presence of wild-type leptin and decouple activation of STAT3 from LepR negative regulators. Together, these results reveal the structural basis for LepR activation and provide insights into the differential plasticity of signaling pathways downstream of LepR.
View details for DOI 10.1038/s41467-023-37169-6
View details for PubMedID 37002197
View details for PubMedCentralID 4859313