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Structural Robustness of Ribosome Functional Centers

Award Number: R01GM094157
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: 09/15/2010
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Structural Robustness of Ribosome Functional Centers - Project Summary The ribosome is the macromolecular machine, conserved throughout evolution, that is responsible for the synthesis of proteins and is therefore a fundamental component of gene expression. Because of its central role in biochemistry, the ribosome has become the target of more than half of all antibiotics, and the evolution of antibiotic resistance due to mutations in the ribosome has become a major threat to human health. Understanding the molecular basis of antibiotic resistance therefore has significant implications for the fight against the threat of resistance. In deciphering the mechanism of antibiotic resistance, fundamental insights into the mechanism of ribosome function can also be acquired, leading to possible novel antimicrobial agents through rational drug design. Through an ongoing collaborative effort, this proposal capitalizes on the ability of the PIs to combine genetics and structural biology to address fundamental questions of ribosome structure and function and provide a framework for future development of novel antimicrobial agents. The Aims of this proposal are: (1) Dissect 30S subunit conformational dynamics during tRNA movement through the ribosome; (2) Define the role of two intersubunit bridges in 30S-50S rotation during translocation; (3) Determine the structural basis for signaling pathways through the ribosome. Achieving these aims will involve exploiting the expertise of the three PIs to generate and characterize functionally impactful mutants and determine their structures by X-ray crystallography or cryo-electron microscopy. The strengths of our proposal include: (1) extensive expertise in the experimental methods to be applied; (2) a long track record of effective collaboration between the PIs; (3) an extensive publication track record in the field of ribosome structure and function; (4) a large volume of preliminary data and ongoing studies, including multiple studies nearing completion. Accomplishing these goals will significantly advance the field by answering long-standing questions about antibiotic resistance mechanisms, while simultaneously expanding our understanding of the basic underlying mechanism of the ribosome.


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 = $360,484 )
2024	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	000	13	8/23/2024	NON-COMPETING CONTINUATION	$360,484
														Subtotal = $360,484

Issue Date FY: 2023 ( Subtotal = $360,712 )
2023	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	000	12	8/28/2023	NON-COMPETING CONTINUATION	$360,712
														Subtotal = $360,712

Issue Date FY: 2022 ( Subtotal = $360,427 )
2022	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	002	11	8/31/2022	NON-COMPETING CONTINUATION	$360,427
2022	2021	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	001	10	4/5/2022	COMPETING CONTINUATION	$26,184
2022	2019	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	000	9	4/5/2022	NON-COMPETING CONTINUATION	-$26,184
														Subtotal = $360,427

Issue Date FY: 2021 ( Subtotal = $386,928 )
2021	2021	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	002	10	8/31/2021	COMPETING CONTINUATION	$386,928
2021	2019	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	001	9	8/25/2021	NON-COMPETING CONTINUATION	$0
2021	2019	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	000	9	4/6/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $386,928

Issue Date FY: 2019 ( Subtotal = $347,344 )
2019	2019	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	000	9	4/11/2019	NON-COMPETING CONTINUATION	$347,344
														Subtotal = $347,344

Issue Date FY: 2018 ( Subtotal = $347,344 )
2018	2018	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	000	8	4/21/2018	NON-COMPETING CONTINUATION	$347,344
														Subtotal = $347,344

Issue Date FY: 2017 ( Subtotal = $347,344 )
2017	2017	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	001	7	7/18/2017	NON-COMPETING CONTINUATION	$34,735
2017	2017	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	000	7	4/14/2017	NON-COMPETING CONTINUATION	$312,609
														Subtotal = $347,344

Issue Date FY: 2016 ( Subtotal = $347,344 )
2016	2016	BROWN UNIVERSITY	POST OFFICE BOX 1929	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	001	6	4/26/2016	COMPETING CONTINUATION	$347,344
2016	2014	BROWN UNIVERSITY	POST OFFICE BOX 1929	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	000	5	4/21/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $347,344

Issue Date FY: 2014 ( Subtotal = $304,722 )
2014	2014	BROWN UNIVERSITY	POST OFFICE BOX 1929	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	000	5	8/25/2014	NON-COMPETING CONTINUATION	$304,722
														Subtotal = $304,722

Issue Date FY: 2013 ( Subtotal = $294,057 )
2013	2013	BROWN UNIVERSITY	POST OFFICE BOX 1929	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	000	4	8/26/2013	NON-COMPETING CONTINUATION	$294,057
														Subtotal = $294,057

Issue Date FY: 2012 ( Subtotal = $304,722 )
2012	2012	BROWN UNIVERSITY	POST OFFICE BOX 1929	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	000	3	8/29/2012	NON-COMPETING CONTINUATION	$304,722
														Subtotal = $304,722

Issue Date FY: 2011 ( Subtotal = $304,722 )
2011	2011	BROWN UNIVERSITY	POST OFFICE BOX 1929	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	000	2	8/26/2011	NON-COMPETING CONTINUATION	$304,722
														Subtotal = $304,722

Issue Date FY: 2010 ( Subtotal = $307,800 )
2010	2010	BROWN UNIVERSITY	POST OFFICE BOX 1929	PROVIDENCE	RI	02912	PROVIDENCE	USA	Biomedical Research and Research Training	000	1	9/13/2010	NEW	$307,800
														Subtotal = $307,800

Grand Total All Awards = $4,373,950

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Structural Robustness of Ribosome Functional Centers

Award Number: R01GM094157

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: 09/15/2010

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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