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Probing the Structural Basis of Innate G Protein Specificity in G Protein-Coupled Receptor Signaling

Award Number: SC2GM130480
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: 06/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Probing the Structural Basis of Innate G Protein Specificity in G Protein-Coupled Receptor Signaling - Probing the Structural Basis of Innate G Protein Specificity in G Protein-Coupled Receptor Signaling Abstract G protein-coupled receptors (GPCRs) are integral membrane proteins that directly couple with their signaling partners like G proteins, GPCR kinases (GRKs), and arrestins, in response to extracellular signals and can trigger multiple intracellular signaling cascades that control a range of vital biological processes. Cells have evolved GPCR-mediated signaling mechanisms, where ligands and receptors play unique functional roles. Each receptor has evolved to activate mainly one subfamily of G proteins, which triggers a specific set of signaling cascades. A ligand is more powerful as it can activate multiple receptor subtypes, which in turn activate multiple set of signaling cascades that causes far reaching cellular effects than a receptor alone. The common feature of ligand and receptor function is the ligand-induced innate G protein specificity of the receptors. This proposal is aimed at probing the G protein specificity of receptor subtypes activated by the same ligand (using muscarinic acetylcholine receptors and dopamine receptors as examples), by the development of computational biophysical methods that will explore thermodynamic and kinetic factors behind the observed G protein selectivities. The methods will provide a structural basis for G protein specificity in dopamine D1 and D2 receptors, which will be used to design receptor mutants with G protein specificity different from that of the wild-type receptors. The methods will be validated by cell based biochemical assays using these mutant receptors and in part by reproducing previously observed switches in G protein selectivity of muscarinic receptor mutants. This mechanistic understanding will have broader implications for many GPCR subfamilies and will lay the foundation for drugs targeting specific therapeutically beneficial receptor – G protein interactions to reduce on-target and off-target side-effects.


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	2022	THE UNIVERSITY CORPORATION	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	3	11/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $145,000 )
2022	2022	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	3	5/12/2022	NON-COMPETING CONTINUATION	$145,000
														Subtotal = $145,000

Issue Date FY: 2021 ( Subtotal = $145,000 )
2021	2021	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	2	5/20/2021	NON-COMPETING CONTINUATION	$145,000
														Subtotal = $145,000

Issue Date FY: 2020 ( Subtotal = $145,000 )
2020	2020	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	5/28/2020	NEW	$145,000
														Subtotal = $145,000

Grand Total All Awards = $435,000

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Probing the Structural Basis of Innate G Protein Specificity in G Protein-Coupled Receptor Signaling

Award Number: SC2GM130480

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: 06/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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