Wednesday, February 18, 2026 2/18/2026

Understanding the structural dynamics of TNF receptors

Award Number: R35GM131814
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2024

Group Awards By:

View Award Description

Understanding the structural dynamics of TNF receptors - 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 MIRA grant will provide flexibility to methodically, and deeply, address fundamental questions regarding TNFR signaling, which will profoundly enhance efforts to identify and rationally target the most vulnerable structural motifs in these important proteins.!


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Biomedical Research and Research Training	000	5	11/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $373,523 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	5	3/14/2023	NON-COMPETING CONTINUATION	$373,523
														Subtotal = $373,523

Issue Date FY: 2022 ( Subtotal = $373,523 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	4	3/18/2022	NON-COMPETING CONTINUATION	$336,166
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	001	4	6/28/2022	NON-COMPETING CONTINUATION	$37,357
														Subtotal = $373,523

Issue Date FY: 2021 ( Subtotal = $373,523 )
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	3	3/29/2021	NON-COMPETING CONTINUATION	$373,523
														Subtotal = $373,523

Issue Date FY: 2020 ( Subtotal = $473,527 )
2020	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	2	6/2/2020	NON-COMPETING CONTINUATION	$373,523
2020	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	001	2	7/23/2020	SUPPLEMENT FOR EXPANSION	$100,004
														Subtotal = $473,527

Issue Date FY: 2019 ( Subtotal = $373,523 )
2019	2019	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	1	5/24/2019	NEW	$373,523
														Subtotal = $373,523

Grand Total All Awards = $1,967,619

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Understanding the structural dynamics of TNF receptors

Award Number: R35GM131814

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2024

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer