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Tools for Enabling Challenging Structure Determination by Cryo-EM

Award Number: R01GM148734
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: 09/19/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Tools for Enabling Challenging Structure Determination by Cryo-EM - Abstract Recent technological innovations have significantly increased the efficiency of cryogenic electron microscopy (cryo-EM), causing a proliferation in the number of structures resolved with ever-increasing resolution. As many of the low hanging fruit structures have been determined, studies have shifted toward increasingly complex specimens, pushing the capabilities of current processing software and requiring novel methodologies. One class of challenging molecule for cryo-EM is tubular molecules that can have ambiguous symmetries. In particular, membrane remodeling proteins that form tubules are often only locally ordered making them intractable for structure determination. Another challenge for cryo-EM structure determination is the problem of the air/water interface. Often when blotting a sample for cryo-EM preparation, the sample can interact with the air/water interface causing protein denaturation, aggregation, or preferred orientations. We have developed a new technique that we are calling reconstruction of average subtracted tubular regions (RASTR) that has the potential to solve both of these problems. RASTR breaks down tubular cryo-EM samples into individual surfaces which enables structure determination without knowing or applying helical symmetry and classification of tubular samples that are only locally ordered with no long-range order. Here we propose two aims to make RASTR more robust, generalizable, and higher-resolution. These aims will be driven by challenging tubular samples that have proven to be intractable to typical cryo-EM structure determination methods. Finally, a third aim is to extend the RASTR approach to single particles bound to tubular substrates in order to protect them from the air/water interface and prevent preferred orientations. Together the proposed aims give RASTR the potential to become a general platform to enable structure determination of challenging samples.


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 = $435,795 )
2025	2025	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	3	8/26/2025	NON-COMPETING CONTINUATION	$435,795
														Subtotal = $435,795

Issue Date FY: 2024 ( Subtotal = $435,795 )
2024	2024	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	2	8/30/2024	NON-COMPETING CONTINUATION	$435,795
														Subtotal = $435,795

Issue Date FY: 2023 ( Subtotal = $449,295 )
2023	2023	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	1	9/18/2023	NEW	$449,295
														Subtotal = $449,295

Grand Total All Awards = $1,320,885

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Tools for Enabling Challenging Structure Determination by Cryo-EM

Award Number: R01GM148734

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: 09/19/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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