# An integrative structural biology approach to the study of T cell signaling

> **NIH NIH R35** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $429,833

## Abstract

Summary
I propose to develop and apply innovative hybrid structural biology tools to investigate the
molecular mechanism of signaling through the T cell receptor (TCR) complex. This is a
fundamental adaptive immunity pathway through which cytotoxic CD8+ T cells can detect the
presence of viruses and developing tumors in the body. Immune function is achieved through
the continuous surveillance of antigen-presenting cells for short peptides displayed within the
molecules of the Major Histocompatibility Complex (MHC) on the cell surface. Key to the initiation
of signaling, is a multi-subunit membrane protein assembly consisting of a clonotypic TCR
heterodimer that recognizes the peptide-MHC, together with the invariant CD3 co-receptor
hexamer that relays an activation signal from the cell surface intracellularly, through the plasma
membrane. Besides the fundamental basic science merit, characterizing this process at atomic
detail has important clinical implications, as is suggested by the large number of
immunodeficiencies resulting from dysregulation of the signaling components and their
interactions.
Despite a large number of functional and structural studies, elucidating the 3D structure of the
signaling complex as a whole remains extremely challenging by conventional methods, due to
its size and dynamic complexity. As a result, the interactions between the TCR and CD3 subunits
and the crucial conformational changes needed for signaling remain incompletely characterized.
With these bottlenecks in mind, I have developed a new methodology combining datasets from
complementary approaches, such as NMR, SANS and cryoEM, together with computational
modeling using the program Rosetta to solve the structures of such challenging complexes.
Here, I propose to apply this powerful integrative approach to elucidate the T cell receptor
complex structure, and to study its dynamic transitions between inactive and active
conformations. My immediate goal is to determine the molecular basis of TCR/CD3 interactions
and to characterize the crucial structural changes in receptor complex arrangement upon antigen
recognition. As a long-term goal, I plan to use a structure-guided approach to engineer novel T
cell receptors with custom specificities and signaling properties, to be used in emerging
immunotherapy applications.

## Key facts

- **NIH application ID:** 9999956
- **Project number:** 5R35GM125034-05
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Nikolaos Sgourakis
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $429,833
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999956

## Citation

> US National Institutes of Health, RePORTER application 9999956, An integrative structural biology approach to the study of T cell signaling (5R35GM125034-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999956. Licensed CC0.

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