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Structural Basis and Molecular Mechanism of GPCR-Arrestin Interactions

Award Number: R35GM151033
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: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Structural Basis and Molecular Mechanism of GPCR-Arrestin Interactions - Project Summary/Abstract G protein coupled receptors are essentially the molecular messengers of the cell, transducing signals from outside to inside. The signals are remarkably diverse, including a single photon, ion like calcium, neurotransmitters and hormones. Humans have more than 800 GPCRs for recognizing different signals, but only three types of transducers, G proteins, GPCR kinases (GRKs) and arrestins. GRKs phosphorylate GPCRs whereas G proteins and arrestins directly bind GPCRs, send the signal to downstream effectors and cause a cellular response. Comparing structures of GPCR bound to G protein and arrestin will provide valuable insights into the functional selectivity and guide the design of more potent drugs with better safety profiles. There are currently >300 structures of GPCR−G protein complex reported but only 8 published structures of GPCR−arrestin complex, which highlights the relative difficulty in obtaining suitable arrestin complexes for structural analysis. My lab focuses on the understudied GPCR−arrestin signaling pathway. We have developed a novel tool which stabilizes GPCR−arrestin complexes for cryo-electron microscopy studies and used that to visualize how the atypical chemokine receptor 3 engages arrestins in various ways at near-atomic resolution. For the next five years, we plan to expand the study to many important GPCR−arrestin pairs to understand the structural details to aid the design of selective interventions. This study will open the way to a detailed dissection of the mechanism of arrestin-mediated GPCR signaling but also to structure-based drug design.


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: 2025 ( Subtotal = $396,250 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Biomedical Research and Research Training	000	3	7/16/2025	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2024 ( Subtotal = $396,250 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Biomedical Research and Research Training	000	2	7/2/2024	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2023 ( Subtotal = $396,250 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Biomedical Research and Research Training	000	1	7/21/2023	NEW	$396,250
														Subtotal = $396,250

Grand Total All Awards = $1,188,750

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Structural Basis and Molecular Mechanism of GPCR-Arrestin Interactions

Award Number: R35GM151033

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: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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