Wednesday, January 28, 2026 1/28/2026

Structural Basis of Signal Instigation Through Family C GPCRs

Award Number: R01NS122394
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: 03/15/2021
PERIOD OF PERFORMANCE END DATE: 09/22/2024

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Structural Basis of Signal Instigation Through Family C GPCRs - Abstract The γ-aminobutyric acid B receptor (GABABR) and the metabotropic glutamate receptors (mGluRs) belong to the Family C of G protein coupled receptors (GPCRs) and critically regulate neuronal excitability, synaptic transmission and plasticity. Many disorders of the CNS have been linked to alterations in neuronal excitability via the glutamatergic and GABAergic system. Accordingly, mGluRs and GABABR have been the subject of an enormous drug discovery effort as they represent major therapeutic targets for treating numerous physiological dysfunctions and for neurodegenerative and neuropsychiatric conditions. Apart from the prototypical seven transmembrane helix (7TM) domain, Family C GPCRs also include a large extracellular ‘venus fly trap’ (VFT) domain that constitutes the orthosteric ligand binding site. Binding of ligand to the extracellular VFT domain triggers a large conformational change in the VFT domains from an open to a closed conformation. This clam- shell like closure of the extracellular domain results in receptor engagement and activation of G proteins on the intracellular side of the transmembrane domain with a mechanism that remains unclear. Receptor activated G proteins then act to either enhance or repress secondary messenger signaling cascades. We recently showed cryoEM structures of near-full length mGluR5 and GABABR in inactive and active conformations, revealing extensive transitions in the organization of the 7TM dimer upon ligand binding to the VFT. Notwithstanding this progress, several key questions remain regarding the allosteric communication across the cell membrane by Family C GPCRs, and particularly the mechanism of G protein coupling and activation. To address these questions, we propose to obtain the structures of mGluR2, mGluR5 and GABABR in complex with their cognate G proteins and probe the structural insights using molecular dynamics simulations and mutagenesis coupled to functional assays. The similarities and differences amongst these receptor-G protein complexes will allow us to contrast and compare our findings and examine aspects of G protein coupling and selectivity. Collectively, these studies will enable us to create a detailed mechanistic framework to understand Family C GPCR signaling and will form the basis for the design of novel therapeutic strategies targeting these receptors.


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 = $0 )
2026	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	12/23/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $698,574 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	006	6	8/1/2025	NON-COMPETING CONTINUATION	$698,575
2025	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	002	4	11/22/2024	NON-COMPETING CONTINUATION	$20,544
2025	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	005	4	2/12/2025	NON-COMPETING CONTINUATION	-$1
2025	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	5	1/17/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	11/21/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$245,360
2025	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	5	11/22/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$20,544
2025	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	4	11/21/2024	NON-COMPETING CONTINUATION	-$245,360
														Subtotal = $698,574

Issue Date FY: 2024 ( Subtotal = $579,919 )
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	4	4/10/2024	NON-COMPETING CONTINUATION	$41,851
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	4	2/13/2024	NON-COMPETING CONTINUATION	$538,068
														Subtotal = $579,919

Issue Date FY: 2023 ( Subtotal = $669,630 )
2023	2023	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	2/6/2023	NON-COMPETING CONTINUATION	$609,072
2023	2023	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	3	2/7/2023	SUPPLEMENT FOR EXPANSION	$60,558
														Subtotal = $669,630

Issue Date FY: 2022 ( Subtotal = $738,944 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/3/2022	NON-COMPETING CONTINUATION	$557,969
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	4/11/2022	SUPPLEMENT FOR EXPANSION	$118,977
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	4/8/2022	NON-COMPETING CONTINUATION	$61,998
														Subtotal = $738,944

Issue Date FY: 2021 ( Subtotal = $703,940 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	8/3/2021	SUPPLEMENT FOR EXPANSION	$58,419
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	8/11/2021	SUPPLEMENT FOR EXPANSION	$0
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/8/2021	NEW	$645,521
														Subtotal = $703,940

Grand Total All Awards = $3,391,007

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Structural Basis of Signal Instigation Through Family C GPCRs

Award Number: R01NS122394

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: 03/15/2021

PERIOD OF PERFORMANCE END DATE: 09/22/2024

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