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Exploring the Dynamics of Prolyl-tRNA Synthetases: Towards Developing a Screening Method for Species-Specific Inhibitors

Award Number: R15GM117510
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: 02/01/2016
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Exploring the Dynamics of Prolyl-tRNA Synthetases: Towards Developing a Screening Method for Species-Specific Inhibitors - The proposed work is the renewal of our previously funded NIH grant proposal. Our research is focused on the interplay between enzyme dynamics and catalysis. For the past twelve years, we have developed techniques and protocols to explore some pressing issues of enzymology − the precise role of dynamics in catalysis, the evolution of functional dynamics across species, and the impact of molecular crowding on catalysis. We are using prolyl-tRNA synthetase (ProRS) as our model enzyme, which belongs to the superfamily of enzymes called aminoacyl-tRNA synthetases (AARSs). Because of their central role in protein synthesis, AARSs have emerged as attractive targets for anti-infective drug development. Common to all kingdoms of life, the active site of ProRSs from different species bear significant sequence similarity. As a result, drug molecules targeting a pathogenic enzyme's catalytic site could bind to the human counterpart, thus resulting in cell toxicity. Therefore, we are attempting to utilize proteins' intrinsic dynamics for designing and screening species-specific inhibitors for pathogenic ProRSs. Currently, the work is at a juncture, where a thorough investigation using state-of-the-art computational techniques, standardized biochemical protocols, and well-established spectroscopic methods could provide deeper insights into the above-mentioned topics. Herein, we propose a comprehensive study, which blends classical and modern biochemical and biophysical techniques to address these core questions of enzymology. The proposed study will investigate in detail the interplay of electrostatics and dynamics in a quest for the evolutionary origin of the enzyme's catalytic power. Additionally, the proposed study will strive to determine the effects of the crowded cellular milieu on our model enzyme. This will be accomplished by following the molecular details of enzymes' conformational dynamics, substrate recognition, and catalysis in crowded and confined environments. Completion of the proposed work could lead to new possibilities for protein design and drug discovery. In addition to the scientific relevance, the proposed work would provide an outstanding opportunity for our students; participation will yield the development of hands-on laboratory skills while deepening their understanding of these fundamental biophysical concepts. Furthermore, the experience and skills acquired through participation will lead to preparedness for the workforce, as well as opportunities to thrive in graduate and professional schools.


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 = -$3,311 )
2025	2021	UNIVERSITY OF WISCONSIN SYSTEM	105 GARFIELD AVENUE	EAU CLAIRE	WI	54701	EAU CLAIRE	USA	Biomedical Research and Research Training	000	2	6/24/2025	COMPETING CONTINUATION	-$3,311
														Subtotal = -$3,311

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF WISCONSIN SYSTEM	105 GARFIELD AVE	EAU CLAIRE	WI	54701	EAU CLAIRE	USA	Biomedical Research and Research Training	001	2	2/14/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2021	UNIVERSITY OF WISCONSIN SYSTEM	105 GARFIELD AVE	EAU CLAIRE	WI	54701	EAU CLAIRE	USA	Biomedical Research and Research Training	000	2	2/14/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $99,900 )
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	105 GARFIELD AVE	EAU CLAIRE	WI	54701	EAU CLAIRE	USA	Biomedical Research and Research Training	000	2	5/23/2023	SUPPLEMENT FOR EXPANSION	$99,900
														Subtotal = $99,900

Issue Date FY: 2021 ( Subtotal = $397,331 )
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	105 GARFIELD AVE	EAU CLAIRE	WI	54701	EAU CLAIRE	USA	Biomedical Research and Research Training	000	2	3/17/2021	COMPETING CONTINUATION	$397,331
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	105 GARFIELD AVE	EAU CLAIRE	WI	54701	EAU CLAIRE	USA	Biomedical Research and Research Training	002	2	9/29/2021	COMPETING CONTINUATION	$952
2021	2016	UNIVERSITY OF WISCONSIN SYSTEM	105 GARFIELD AVE	EAU CLAIRE	WI	54701	EAU CLAIRE	USA	Biomedical Research and Research Training	001	1	9/29/2021	NEW	-$952
														Subtotal = $397,331

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2016	UNIVERSITY OF WISCONSIN SYSTEM	105 GARFIELD AVE	EAU CLAIRE	WI	54701	EAU CLAIRE	USA	Biomedical Research and Research Training	000	1	1/16/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $380,899 )
2016	2016	UNIVERSITY OF WISCONSIN, EAU CLAIRE	105 GARFIELD AVENUE	EAU CLAIRE	WI	54701	EAU CLAIRE	USA	Biomedical Research and Research Training	001	1	4/14/2016	NEW	$43,908
2016	2016	UNIVERSITY OF WISCONSIN, EAU CLAIRE	105 GARFIELD AVENUE	EAU CLAIRE	WI	54701	EAU CLAIRE	USA	Biomedical Research and Research Training	000	1	1/11/2016	NEW	$336,991
														Subtotal = $380,899

Grand Total All Awards = $874,819

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Exploring the Dynamics of Prolyl-tRNA Synthetases: Towards Developing a Screening Method for Species-Specific Inhibitors

Award Number: R15GM117510

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: 02/01/2016

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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