# Understanding the structural dynamics of TNF receptors

> **NIH NIH R35** · UNIVERSITY OF MINNESOTA · 2021 · $373,523

## Abstract

ABSTRACT
The tumor necrosis factor receptors (TNFRs) are a superfamily of transmembrane proteins that play critical roles
in apoptosis and inflammatory diseases and are considered important therapeutic targets. Even though targeting
of TNFRs is a billion-dollar industry, the clinically available drugs cause devastating side effects because they
lack receptor specificity. My research focuses on understanding the essential conformational dynamics of TNFRs
that transduce signals across the membrane, with the ultimate goal of enabling highly effective and specific
targeting. To accelerate scientific discovery, we have focused on two of the most clinically relevant members of
the superfamily: TNFR1, involved in various autoimmune diseases, including rheumatoid arthritis; and Death
Receptor 5, one of the most actively pursued anti-cancer targets. We apply an investigative strategy that includes
computational molecular modeling, thermodynamic calculations, and in vitro experimental tools, enabling us to
predict and understand conformational changes in these single-pass transmembrane proteins. Our work has
yielded important findings published in high-impact journals. For instance, we elucidated mechanisms of ligand
binding in both TNFR1 and DR5. We found that binding is controlled by an interaction between methionine and
aromatic amino acids, causing a conformational rearrangement of the ligand-binding pocket. Our studies of this
interaction motif led to a fundamental discovery that answered a long-standing question regarding the role of
methionine in protein folding, and further, how methionine oxidation causes protein misfolding. We built a new
model of TNFR oligomerization that led us to discover that ligand binding causes a large-scale backbone
conformational change in the extracellular domain of the receptor. This finding revised previous assumptions
regarding TNFRs that activation occurs without any conformational changes in the receptor backbone. With
computation and biophysical and cellular experiments, we also showed for the first time a scissors-like opening
that occurs in the transmembrane domain helices and explained the fundamental thermodynamics of this
process. Significantly, using FRET-based small molecule discovery, we built on our new model of TNFR
activation and showed that allosteric alteration of the conformational states of TNFRs can inhibit activation, and
have thereby opened new avenues to therapeutic intervention. We propose to extend our discoveries by
integrating the dynamic modes across domains of the receptor and answering the fundamental question: what
is the structural and dynamic mechanism of TNFR activation? We will address impactful questions, some of
which may be high-risk, but with potential to be transformative in the field and to launch new directions in drug
discovery. Our productivity is enhanced by longstanding interdisciplinary collaborations that engage additional
biophysical tools, including EPR and NMR. The MI...

## Key facts

- **NIH application ID:** 10178044
- **Project number:** 5R35GM131814-03
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Jonathan N Sachs
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $373,523
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10178044

## Citation

> US National Institutes of Health, RePORTER application 10178044, Understanding the structural dynamics of TNF receptors (5R35GM131814-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10178044. Licensed CC0.

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