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Structure Determination of G Protein-Coupled Receptors by Microcrystal Electron Diffraction

Award Number: R01GM124152
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: 09/30/2017
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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Structure Determination of G Protein-Coupled Receptors by Microcrystal Electron Diffraction - SUMMARY The overall aim of this project is to use the recently developed cryo-electron microscopy technique of microcrystal electron diffraction (MicroED) for the structure determination of G protein-coupled receptors (GPCR). GPCRs are an extremely important class of membrane proteins and are responsible for controlling a wide variety of physiological responses. Because of their key physiological roles, a large percentage of currently approved drugs target these receptors, and they represent attractive targets for drug development. Despite the importance of GPCRs, detailed understanding of their high resolution structure and function is limited in large part because of the difficulty associated growing large crystals necessary for X-ray crystallography. In this project, MicroED will be used to study GPCR structure, as the method is capable of determining structures from microcrystals several orders of magnitude smaller than those used by conventional X-ray crystallography. The project will employ and optimize new MicroED sample preparation methodology to allow data collection from GPCR microcrystals grown in the viscous lipidic cubic phase (LCP). Electron diffraction data will be collected and processed using previously developed MicroED methods. The new methods for GPCRs will be validated in Aim 1 using the previously solved beta-2 adrenergic receptor (β2AR) and A2A Adenosine receptor (A2AAR) as models. New structural details will be studied in Aims 2 and 3 by using MicroED to improve the resolution and modeling of the rhodopsin-arrestin complex (Aim 2), and finally to determine a novel structure of the serotonin receptor 5HT4 (Aim 3). The long term goal of this project is to develop and use MicroED as a high-throughput structure determination method for GPCRs and other important membrane proteins grown in LCP. By determining the structures outlined in these aims, not only will new light will be shed on GPCR structure and function, but the optimized protocols will open the door to MicroED analysis for a variety of membrane protein samples. This will make MicroED a valuable tool for membrane protein structure determination of targets that have resisted other structural methods because of difficulties with optimizing crystal size for X-ray crystallography.


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 = -$3,021 )
2024	2021	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	000	5	3/18/2024	NON-COMPETING CONTINUATION	-$3,021
														Subtotal = -$3,021

Issue Date FY: 2021 ( Subtotal = $297,190 )
2021	2021	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	000	5	6/24/2021	NON-COMPETING CONTINUATION	$297,190
														Subtotal = $297,190

Issue Date FY: 2020 ( Subtotal = $297,999 )
2020	2020	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	000	4	6/10/2020	NON-COMPETING CONTINUATION	$297,999
														Subtotal = $297,999

Issue Date FY: 2019 ( Subtotal = $298,748 )
2019	2019	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	000	3	7/8/2019	NON-COMPETING CONTINUATION	$298,748
														Subtotal = $298,748

Issue Date FY: 2018 ( Subtotal = $447,872 )
2018	2018	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	001	2	9/13/2018	SUPPLEMENT FOR EXPANSION	$149,184
2018	2018	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	000	2	7/9/2018	NON-COMPETING CONTINUATION	$298,688
														Subtotal = $447,872

Issue Date FY: 2017 ( Subtotal = $298,415 )
2017	2017	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	000	1	9/13/2017	NEW	$298,415
														Subtotal = $298,415

Grand Total All Awards = $1,637,203

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Structure Determination of G Protein-Coupled Receptors by Microcrystal Electron Diffraction

Award Number: R01GM124152

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: 09/30/2017

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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