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Development of Cryo-EM/TEM Technologies for Small Protein and RNA Systems

Award Number: R01GM125907
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: 01/01/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Development of Cryo-EM/TEM Technologies for Small Protein and RNA Systems - Abstract While a recent “resolution revolution” has catapulted the use of cryo-EM imaging for high-resolution structure solution of biomolecules, these advances have mostly been restricted to studies of relatively large complexes (e.g. ribosome, spliceosome, and viral particles). Properties of these complexes, such as having a molecular weight >200 kD and inherent stability, make them ideal targets for cryo-EM, which utilizes the averaging of data from tens/hundreds of thousands of particles to reconstruct their 3D structure. However, the vast majority of molecules-of-interest do not have these properties, and have thus remained ignored and considered intractable for cryo-EM studies. Here, design and initial development of four technologies that can overcome these hurdles to make the cryo- EM imaging practical to the research and biomedical communities are described. First, inspiration has been taken from viral particles to produce a rigid and versatile scaffold for the capture and presentation of proteins via a “plug-and-play” approach. Because this approach does not require genetic fusion of each new protein-of- interest to the scaffold, “average-sized” proteins and their variants can be rapidly screened for structural study. Here these technologies will be advanced using molecules from the PIs' field of expertise (protein/RNA biology), but these scaffolds and methods can be applied to any functional class of proteins-of-interest. Second, a rigid and versatile scaffold for the capture and presentation of nucleic acids has been produced. Technologies based upon this scaffold will open the doors to cryo-EM imaging of folded RNAs that have been heretofore considered too small for cryo-EM and transmission EM (TEM) studies. Moreover, structural studies and measurements of the in vivo variance of RNA folding populations in cells will be determined using these technologies. In this proposed work, technologies will be developed for wide scale use by the community by determining and optimizing the parameters that affect their use in cryo-EM and TEM studies of proteins and RNA. Ultimately, these rigid, highly symmetrical, and versatile scaffolds, and the methodologies for their optimal use, will drive down the lower practical size limits of cryo-EM and enable researchers to address a wide range of biological questions specific to their respective fields.


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 = $0 )
2024	2021	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	4	7/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	4	12/2/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $539,971 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	4	3/2/2021	NON-COMPETING CONTINUATION	$53,998
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	4	12/8/2020	NON-COMPETING CONTINUATION	$485,973
														Subtotal = $539,971

Issue Date FY: 2020 ( Subtotal = $546,917 )
2020	2020	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	3	3/11/2020	NON-COMPETING CONTINUATION	$54,692
2020	2020	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	3	12/19/2019	NON-COMPETING CONTINUATION	$492,225
														Subtotal = $546,917

Issue Date FY: 2019 ( Subtotal = $561,102 )
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	2	1/8/2019	NON-COMPETING CONTINUATION	$561,102
														Subtotal = $561,102

Issue Date FY: 2018 ( Subtotal = $546,434 )
2018	2018	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	1	12/30/2017	NEW	$546,434
														Subtotal = $546,434

Grand Total All Awards = $2,194,424

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Development of Cryo-EM/TEM Technologies for Small Protein and RNA Systems

Award Number: R01GM125907

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: 01/01/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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