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G protein coupled receptor structure, dynamics, and signaling.

Award Number: R35NS137408
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2032

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G protein coupled receptor structure, dynamics, and signaling. - Project Summary G protein coupled receptors (GPCRs) are the largest family of receptors for neurotransmitters and hormones, and are therefore the largest group of targets for new therapeutics for a very broad spectrum of diseases including neurologic, cardiovascular, pulmonary and metabolic disorders. While initially thought to signal exclusively through G proteins and function as two-state switches activated by hormones and neurotransmitters, research over the past 30 years has revealed that most GPCRs have complex and diverse signaling behaviors. A single GPCR can activate more than one G protein subtype as well as G protein independent signaling pathways such as arrestins. Many GPCRs exhibit basal, agonist-independent activity. When considering one of the several possible downstream signaling pathways, a drug acting at the orthosteric binding pocket may exhibit one of four efficacy profiles. It may behave as an inverse agonist, suppressing basal activity, a full agonist, maximally activating the pathway, a partial agonist, promoting submaximal activity even at saturating concentrations, or a neutral antagonist, having no effect on basal signaling, but blocking the binding of other orthosteric ligands. The efficacy profile of a given ligand may differ for different signaling pathways such that a drug may behave as an agonist for a specific G protein subtype or arrestin while have no effect or inhibiting other signaling pathways. This pathway selective (or biased) signaling has become an important consideration for drug discovery, since one signaling pathway may produce therapeutic effects while another may lead to adverse effects. During the previous funding period we have applied cryo-electron microscopy and several biophysical methods to characterize the structure and dynamic character of several Family A GPCRs, as well as a Family B and Family C GPCR. These studies provide evidence that these GPCRs are highly dynamic and conformationally complex. We hypothesize that this complexity is essential for their functional versatility, and believe that a more detailed understanding of this complex conformational landscape will provide mechanistic insights into targeted activation of a specific pathway with biased ligands. The goal of this proposal will be to understand the structural basis for GPCR signaling through multiple pathways using methods that will provide high-resolution structural constraints and characterize protein dynamics under more physiologic conditions.


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: 2026 ( Subtotal = $627,837 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/1/2026	NON-COMPETING CONTINUATION	$627,837
														Subtotal = $627,837

Issue Date FY: 2025 ( Subtotal = $627,837 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/16/2025	NON-COMPETING CONTINUATION	$627,837
														Subtotal = $627,837

Issue Date FY: 2024 ( Subtotal = $627,837 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	5/14/2024	NEW	-$14,467
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/8/2024	NEW	$642,304
														Subtotal = $627,837

Grand Total All Awards = $1,883,511

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G protein coupled receptor structure, dynamics, and signaling.

Award Number: R35NS137408

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2032

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