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Structural dynamics underlying GPCR-G protein selectivity

Award Number: R01GM117923
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: 05/17/2017
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Structural dynamics underlying GPCR-G protein selectivity - Summary: Title: Structural dynamics underlying GPCR-G protein selectivity Upon binding to agonists with different efficacies, G protein-coupled receptors (GPCRs) mediate multiple signaling pathways by coupling to different subtypes of G proteins. Certain agonists exhibit selectivity in their efficacy to specific G-protein signaling pathways. Such ligands provide precise therapeutic benefits with fewer side effects as drugs compared to today's GPCR-targeted drugs. There are very few selective ligands known for specific G-protein signaling pathways because designing such agonists is a daunting experimental challenge. This is due to serious lack of understanding of how GPCRs modulate their functional selectivity for their cognate G-protein when bound to different type of agonists and in cells. In the past three years using a combination of multiscale molecular dynamics (MD) method and genetically coded FRET sensors we have shown that GPCRs have latent intracellular cavities that can reshape and couple to different G-proteins. By reengineering G-proteins and GPCRs we have identified the hotspot residues in the GPCR-G-protein interface that serve as the “QR code” for G-protein selective coupling by GPCRs. Although it is clear that allosteric communication from the ligand binding site to the G-protein coupling site plays a role in G-protein selectivity very little is known about the mechanism of this communication and the residues involved in this process. Here we propose to (1) use the computational method Allosteer developed in our lab in combination with FRET sensors, NanoBRET assays and cell based downstream assays to delineate the allosteric network of GPCR residues involved in regulating G-protein selectivity in 9 different Gs, Gi and Gq coupled class A GPCRs in cellular conditions. The second aim is to understand the effect of partial agonists in comparison to the full agonists, on the GPCR-G-protein selective coupling. We will identify the hotspot residues on the G-protein and GPCRs when bound to partial agonists and compare the similarities and differences with full agonists. The outcome of the proposed work will provide the role of allosteric network of residues in G-protein selectivity and how partial agonists modulate the receptor conformations. This will push forward our understanding of the biological process of how GPCRs recognize their cognate G-proteins in live cells.


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 = $352,000 )
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	001	8	6/7/2024	NON-COMPETING CONTINUATION	$35,200
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	000	8	12/26/2023	NON-COMPETING CONTINUATION	$316,800
														Subtotal = $352,000

Issue Date FY: 2023 ( Subtotal = $352,000 )
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	001	7	2/15/2023	NON-COMPETING CONTINUATION	$35,200
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	000	7	1/10/2023	NON-COMPETING CONTINUATION	$316,800
														Subtotal = $352,000

Issue Date FY: 2022 ( Subtotal = $352,000 )
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	000	6	2/1/2022	NON-COMPETING CONTINUATION	$316,800
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	006	6	7/1/2022	NON-COMPETING CONTINUATION	$35,200
2022	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	004	4	6/29/2022	NON-COMPETING CONTINUATION	$0
2022	2019	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	005	3	6/29/2022	NON-COMPETING CONTINUATION	$0
2022	2019	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	002	3	6/29/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2018	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	003	2	6/29/2022	NON-COMPETING CONTINUATION	$0
2022	2017	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	001	1	6/29/2022	NEW	$0
														Subtotal = $352,000

Issue Date FY: 2021 ( Subtotal = $344,400 )
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	000	5	3/29/2021	COMPETING CONTINUATION	$344,400
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	002	5	8/29/2021	COMPETING CONTINUATION	$8,255
2021	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	001	4	8/29/2021	NON-COMPETING CONTINUATION	-$8,255
														Subtotal = $344,400

Issue Date FY: 2020 ( Subtotal = $551,908 )
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	1/30/2020	NON-COMPETING CONTINUATION	$496,716
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	001	4	3/10/2020	NON-COMPETING CONTINUATION	$55,192
														Subtotal = $551,908

Issue Date FY: 2019 ( Subtotal = $667,026 )
2019	2019	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	001	3	8/7/2019	SUPPLEMENT FOR EXPANSION	$110,000
2019	2019	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	000	3	1/14/2019	NON-COMPETING CONTINUATION	$557,026
														Subtotal = $667,026

Issue Date FY: 2018 ( Subtotal = $556,493 )
2018	2018	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	001	2	5/24/2018	NON-COMPETING CONTINUATION	$55,651
2018	2018	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	000	2	1/11/2018	NON-COMPETING CONTINUATION	$500,842
														Subtotal = $556,493

Issue Date FY: 2017 ( Subtotal = $587,009 )
2017	2017	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	5/17/2017	NEW	$587,009
														Subtotal = $587,009

Grand Total All Awards = $3,762,836

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Structural dynamics underlying GPCR-G protein selectivity

Award Number: R01GM117923

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: 05/17/2017

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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