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Elucidating the Mechanistic Details of the Grp94 Molecular Chaperone through an Integrated Computational and Experimental Approach

Award Number: R35GM146963
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Chaperone proteins are critical for cell survival and provide pathways for correct protein folding within the cell. Our research focuses on ATP-dependent chaperones in the endoplasmic reticulum, specifically Grp94. Grp94 belongs to the highly conserved Hsp90 superfamily, and like its cytosolic and mitochondrial paralogs, it folds and activates specific client proteins. Grp94 is of fundamental interest because it has limited mechanistic information compared to other paralogs. Grp94 is also unique because it has several observed structural and functional differences from paralogs that make it a promising drug target. Despite the importance of Grp94 chaperoning in protein homeostasis, the fundamental details of its chaperone cycle are not well characterized. Grp94 is of practical interest since aberrant protein folding in the endoplasmic reticulum results in medical issues such as type 2 diabetes, cancer, hepatitis B & C, and neurodegenerative and cardiovascular diseases. Understanding Grp94’s structure and function will provide a foundation for understanding how diseases caused by misfolded ER proteins can be treated and prevented. This fundamental knowledge of Grp94 mechanisms can aid in rational drug design. Current strategies involve ATP-competitive inhibitors that target all Hsp90 paralogs and inhibit both productive and unproductive chaperone activity, which results in toxicity. Novel therapeutic strategies include inhibiting chaperoning of toxic proteins while retaining chaperoning of non-toxic proteins and targeting specific Hsp90 paralogs; however, mechanistic information is required to move the field in this direction. Therefore, the studies of this chaperone mechanism will be of immense practical and economical value in the development of disease therapies. Understanding the conformational changes involved in the chaperone cycle is fundamentally important for identifying points of intervention. Understanding how client proteins and other chaperones structurally and functionally interact is fundamentally important for designing competitive modulators of Grp94. My lab will develop novel techniques for functional and structural studies of Grp94. We will tightly couple experimental and computational studies, which is a powerful combination of tools that will enable us to elucidate molecular details that wouldn’t be possible to obtain with either method individually. Using this approach, we will answer the following pertinent biological questions: (1) What are the preferred conformational states of Grp94 and which conformations co-exist in equilibrium? (2) How do cellular conditions and interactors influence Grp94’s conformational sampling? (3) What type of chaperone activity does Grp94 demonstrate and what are the requirements? (4) Where do client proteins interact on Grp94? (5) Are ATP hydrolysis events in the Grp94 dimer symmetric or asymmetric? The successful completion of these studies is expected to have an important impact in deconvoluting the Grp94 chaperone mechanism, the structural changes involved, and the details of substrate protein interactions and processing. This information will facilitate in finding new and novel points of intervention to ameliorate disease.


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: 2024 ( Subtotal = $343,784 )
2024	2024	MIAMI UNIVERSITY	501 E HIGH ST	OXFORD	OH	45056	BUTLER	USA	Biomedical Research and Research Training	000	3	6/21/2024	NON-COMPETING CONTINUATION	$343,784
														Subtotal = $343,784

Issue Date FY: 2023 ( Subtotal = $343,784 )
2023	2023	MIAMI UNIVERSITY	501 E HIGH ST	OXFORD	OH	45056	BUTLER	USA	Biomedical Research and Research Training	000	2	6/27/2023	NON-COMPETING CONTINUATION	$343,784
														Subtotal = $343,784

Issue Date FY: 2022 ( Subtotal = $309,885 )
2022	2022	MIAMI UNIVERSITY	501 E HIGH ST	OXFORD	OH	45056	BUTLER	USA	Biomedical Research and Research Training	000	1	7/29/2022	NEW	$309,885
														Subtotal = $309,885

Grand Total All Awards = $997,453

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Elucidating the Mechanistic Details of the Grp94 Molecular Chaperone through an Integrated Computational and Experimental Approach

Award Number: R35GM146963

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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