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Discovering the mechanism of GPCR-mediated arrestin stimulation to enable effective drug therapies

Award Number: R01GM127359
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 Medicines that cause G protein–coupled receptors (GPCRs) to selectively stimulate arrestins, or to selectively avoid stimulation of arrestins, promise more effective and safer treatments for a wide variety of diseases, including neuropsychiatric, cardiovascular, pulmonary and metabolic disorders. Despite intense study of GPCR–arrestin interactions in both academia and the pharmaceutical industry, and despite dramatic recent advances in the structural biology of GPCRs and arrestins, the mechanism by which GPCRs stimulate arrestins remains poorly understood. Likewise, the means by which GPCRs might achieve selectivity for or against arrestin signaling remains unclear. The proposed research will utilize atomic-level molecular dynamics simulations to address these challenges, thereby providing a foundation for the design of functionally selective GPCR-targeted drugs with desired effects on arrestins. Aim 1 is to determine the activation mechanism of arrestin, pinpointing which of the GPCR– arrestin interaction surfaces drives arrestin activation and discovering the allosteric coupling between regions of arrestin that causes these structural changes to take place. The remaining aims are to determine the effect of both GPCR conformation (Aim 2) and GPCR phosphorylation pattern (Aim 3) on arrestin binding and activation. This will reveal how a GPCR can favor or disfavor arrestin recruitment and signaling relative to G protein recruitment and signaling. It will also reveal how a GPCR can favor specific arrestin conformations, potentially stimulating some of arrestin’s downstream effects without stimulating others. The proposed research will rely on state-of-the-art simulation methods that have recently enabled the determination of functional mechanisms of GPCRs, G proteins, transporters, and other proteins. It will also benefit from close collaborations with multiple experimentalists: results from crystallography, fluorescence spectroscopy, NMR, electron paramagnetic resonance, and cell signaling experiments will combine to both guide and validate the simulations. This proposal is significant not only because it will illuminate a quintessential biological signaling process but also because it will reveal a key part of the structural basis for functional selectivity at GPCRs. It will thus provide a foundation for the rational design of safer and more effective medications acting at GPCRs, which are by far the largest class of drug targets.


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: 2022 ( Subtotal = $311,720 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	5	1/13/2022	NON-COMPETING CONTINUATION	$280,548
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	5	7/20/2022	NON-COMPETING CONTINUATION	$31,172
														Subtotal = $311,720

Issue Date FY: 2021 ( Subtotal = $309,440 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	4	1/29/2021	NON-COMPETING CONTINUATION	$278,496
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	4	2/11/2021	NON-COMPETING CONTINUATION	$30,944
														Subtotal = $309,440

Issue Date FY: 2020 ( Subtotal = $309,440 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	3	1/30/2020	NON-COMPETING CONTINUATION	$278,496
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	3	3/5/2020	NON-COMPETING CONTINUATION	$30,944
														Subtotal = $309,440

Issue Date FY: 2019 ( Subtotal = $309,440 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	2	12/31/2018	NON-COMPETING CONTINUATION	$309,440
														Subtotal = $309,440

Issue Date FY: 2018 ( Subtotal = $308,072 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	1	3/23/2018	NEW	$308,072
														Subtotal = $308,072

Grand Total All Awards = $1,548,112

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Discovering the mechanism of GPCR-mediated arrestin stimulation to enable effective drug therapies

Award Number: R01GM127359

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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