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High Resolution Structure Determination of Non-Coding RNAs to Reveal Functional Mechanisms

Award Number: R35GM141706
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: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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High Resolution Structure Determination of Non-Coding RNAs to Reveal Functional Mechanisms - PROJECT SUMMARY/ABSTRACT RNA structure is involved in all aspects of the central dogma of molecular biology. However, there are relatively few unique RNA structures determined at high resolution that would give detailed insight into functional mechanisms. We are focused on studying RNA structure/function relationships via two major themes: Theme #1: Determine the architectures of protein-free non-coding RNAs at high resolution to gain insight into in vivo function. Cryo-EM of protein-free RNAs is difficult with only a handful of structures determined to better than 4 angstroms. We have developed a scaffolding methodology that enables us to determine cryo-EM structures of protein-free RNAs to 2.5 angstroms resolution routinely. This now enables us to delineate precise structure function relationships at the individual nucleotide level for non-coding RNAs. Using this pipeline, we are targeting bacterial and human non-coding RNAs that have significant biological impacts. A bacterial non-coding RNA known as raiA is necessary for sporulation and biofilm formation. We are using structural biology, in vitro biochemistry, and in vivo biology to interrogate its involvement in these processes. Our scaffolding methodology is also being applied to the untranslated regions (UTRs) of human RNAs encoding proteins. As part of our preliminary studies, we have determined structures of human UTRs that have significant effects upon gene expression. These pilot studies show that human RNAs contain highly structured domains that are important for gene regulation. Theme #2: Investigate mechanisms that are part of the central dogma of molecular biology, such as translation, splicing, and cDNA synthesis. We are studying the molecular mechanism of peptide bond formation in the ribosome. We have discovered structural evidence for metal ion catalysis in the ribosome with mechanistic and active site similarities to RNA splicing. We will use this metal ion model as a guide for the design of biochemical experiments to probe the mechanism of peptide bond formation in the ribosome. In addition, consistent with our interests in retrotransposition, we are studying novel priming mechanisms in reverse transcriptases involved in phage defense. In summary, we are investigating the biological and biochemical significance of RNA structure in cellular processes across the different kingdoms of life.


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 = $566,034 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	6	4/22/2026	COMPETING CONTINUATION	$566,034
														Subtotal = $566,034

Issue Date FY: 2025 ( Subtotal = $395,000 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	5	3/31/2025	NON-COMPETING CONTINUATION	$395,000
2025	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	11/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $395,000

Issue Date FY: 2024 ( Subtotal = $464,283 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	3/8/2024	NON-COMPETING CONTINUATION	$355,500
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	002	4	7/23/2024	NON-COMPETING CONTINUATION	$39,500
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	4	6/25/2024	SUPPLEMENT FOR EXPANSION	$69,283
														Subtotal = $464,283

Issue Date FY: 2023 ( Subtotal = $395,000 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	3	3/16/2023	NON-COMPETING CONTINUATION	$395,000
														Subtotal = $395,000

Issue Date FY: 2022 ( Subtotal = $395,000 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	3/16/2022	NON-COMPETING CONTINUATION	$355,500
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	2	7/21/2022	NON-COMPETING CONTINUATION	$39,500
														Subtotal = $395,000

Issue Date FY: 2021 ( Subtotal = $403,672 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	3/26/2021	NEW	$403,672
														Subtotal = $403,672

Grand Total All Awards = $2,618,989

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High Resolution Structure Determination of Non-Coding RNAs to Reveal Functional Mechanisms

Award Number: R35GM141706

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: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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