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Deciphering fundamental biological processes involving protein-nucleic acid interactions at the molecular level

Award Number: R35GM130290
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT The central goal of the Schumacher laboratory is to deduce principles governing fundamental biological processes involving protein-nucleic acid interactions and their regulation, with a particular focus on processes important in microbial pathogenesis. While we aim to elucidate these mechanisms at the atomic level, it is critical that we are able to place our molecular findings within a biologically relevant context. Importantly, the elucidation of such physiologically relevant mechanisms also provides molecular targets for the development of antimicrobial agents, which are urgently needed; recent estimates suggest that deaths from antimicrobial resistance (AMR) bacteria may exceed 10 million deaths worldwide by 2050 if steps are not taken to generate new treatments. Microbes must be able to sense and respond to environmental changes for their survival and in some cases, proper development. Hence, our studies focus on essential processes in which environmental cues are signaled and detected. Recent studies have shown that the metabolic state of bacteria influences their susceptibility to antibiotics and that antibiotic efficacy can be enhanced by altering the metabolic state of bacteria. A main area of interest in the lab has been elucidating the mechanisms by which essential elements, such as nitrogen, are sensed and regulated in microbes. The central enzyme in nitrogen homeostasis is glutamine synthetase (GS), which catalyzes the assimilation of ammonium ions into glutamine, and thus serves as the major nitrogen donor for the generation of all key metabolites. Using a combination of cryo-EM, X-ray crystallography, biochemistry and in vivo studies, we have dissected the GS-GlnR signaling pathway in bacteria and uncovered a novel mechanism of dual regulation involving altered oligomerization of both proteins. We term this form of regulation, “oligomer modulation”. We have gone on to show that oligomer modulation may, in fact, be a commonly used mode of GS regulation. Specifically, we found that the Methanosarcina mazei (Mm) GS, which forms a large dodecameric machine at high concentrations, is present as inactive dimers at physiologically relevant concentrations. This mechanism was suggested by our structural studies, which were performed at high concentrations. However, mass photometry (MP) permitted an analysis of the GS oligomer state at physiological levels. This study thus shows the power of MP in placing our structural findings within a biological framework. MP could be utilized in all our studies to assess complexes and oligomers and as a result to aid in the development of biologically relevant macromolecular models that can be targeted for drug development.


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	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	000	7	11/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $886,751 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	002	7	7/17/2024	SUPPLEMENT FOR EXPANSION	$239,000
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	000	7	11/30/2023	NON-COMPETING CONTINUATION	$582,976
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	001	7	6/25/2024	NON-COMPETING CONTINUATION	$64,775
														Subtotal = $886,751

Issue Date FY: 2023 ( Subtotal = $656,315 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	003	6	8/31/2023	COMPETING CONTINUATION	$268,360
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	002	5	8/24/2023	NON-COMPETING CONTINUATION	-$193,975
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	000	5	1/6/2023	NON-COMPETING CONTINUATION	$523,738
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	001	5	3/31/2023	NON-COMPETING CONTINUATION	$58,192
														Subtotal = $656,315

Issue Date FY: 2022 ( Subtotal = $581,930 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	4	12/22/2021	NON-COMPETING CONTINUATION	$523,737
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	001	4	7/20/2022	NON-COMPETING CONTINUATION	$58,193
														Subtotal = $581,930

Issue Date FY: 2021 ( Subtotal = $581,930 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	001	3	3/10/2021	NON-COMPETING CONTINUATION	$58,193
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	3	12/17/2020	NON-COMPETING CONTINUATION	$523,737
														Subtotal = $581,930

Issue Date FY: 2020 ( Subtotal = $581,930 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	2	1/14/2020	NON-COMPETING CONTINUATION	$581,930
														Subtotal = $581,930

Issue Date FY: 2019 ( Subtotal = $316,002 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	1	12/27/2018	NEW	$316,002
														Subtotal = $316,002

Grand Total All Awards = $3,604,858

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Deciphering fundamental biological processes involving protein-nucleic acid interactions at the molecular level

Award Number: R35GM130290

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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