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Emergent role of allostery on function of GPCRs and Trimeric G proteins

Award Number: R35GM156498
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: 02/01/2025
PERIOD OF PERFORMANCE END DATE: 01/31/2030

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Emergent role of allostery on function of GPCRs and Trimeric G proteins - Project Summary The structural biology revolution in G protein coupled receptors (GPCRs) over the last two decades has pipelined a number of allosteric GPCR ligands into FDA clinical trials. Over 500 GPCR-G protein complexes are now publicly accessible and represent only the ‘tip of the iceberg’ of structures capturing ligand-GPCR-G protein complexes in biopharma. Despite this information explosion, these structures only provide static snap shots that do not capture the dynamic conformational landscape and allosteric communication that underlie the mechanism of drug action. Further, the quest of understanding the G protein coupling selectivity by GPCRs has necessitated enquiry into the role of sequence-divergent disordered structural regions of GPCRs that are not resolved in high-resolution structures. To address these challenges, we have developed innovative computational methods including AI centered techniques. Building on these new technologies and conceptual advances from my lab, we propose the following parallel research projects. (1) We have shown that the temporal coupling frequency of GPCR-G protein interactions and allosteric communication modulate the G protein coupling selectivity by GPCRs. Going forward we will dissect the structural basis of the allosteric modulation by the third intracellular loop (ICL3). We will define roles for ICL3 in autoregulation and G protein selection in closely related receptors. (2) Our extensive studies in identifying allosteric hotspot residues in GPCRs involved in allosteric communication has yielded a procedure for locating cryptic binding sites with allosteric communication propensity. Going forward we will exploit these findings to develop a systematic workflow to identify allosteric modulator binding sites. To demonstrate the use of the workflow we will also develop allosteric modulators for GPCRs. Our strong preliminary data shows that this project will lead to a reliable workflow that can be used to identify allosteric modulators for GPCRs. This workflow will also be broadly applicable to other proteins. (3) Our studies on trimeric G proteins have shown that disease associated residue mutations allosteric to the nucleotide binding site have a profound effect on the activation mechanism of G proteins. Going forward we propose to dissect the similarities and differences in mechanism of Gβγ dissociation from Gα subunit and the effect of mutations on this dissociation process.


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 = $400,500 )
2026	2026	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	001	2	1/22/2026	NON-COMPETING CONTINUATION	$400,500
2026	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	1/19/2026	NEW	$0
														Subtotal = $400,500

Issue Date FY: 2025 ( Subtotal = $445,000 )
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	1/28/2025	NEW	$445,000
														Subtotal = $445,000

Grand Total All Awards = $845,500

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Emergent role of allostery on function of GPCRs and Trimeric G proteins

Award Number: R35GM156498

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: 02/01/2025

PERIOD OF PERFORMANCE END DATE: 01/31/2030

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