Tuesday, April 23, 2024 4/23/2024

Dynamic modulation of p53 activity by its disordered regulatory domains

Award Number: R01GM075995
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

Approximately 30% of the proteins in the human proteome are intrinsically disordered (IDPs) or contain long disordered regions (IDRs). IDPs play a central role in key cellular regulatory pathways and are implicated in devastating diseases such as cancer, diabetes, cardiovascular disease, and neurodegenerative disease. Disordered proteins are highly flexible and undergo transient and dynamic intramolecular and intermolecular interactions that are central to their regulatory functions. Molecular level characterization of the numerous human regulatory proteins that contain both structured and disordered domains represents an enormous challenge to the traditional methods of structural biology. Most studies to date have relied upon a reductionist approach, in which the ordered and disordered regions are investigated in isolation. However, within the cell, the different domains of a given protein act synergistically to allow it to perform its biological function and a full understanding of the underlying molecular mechanism can only be achieved through a holistic, rather than reductionist, approach. The overarching goal of this proposal is to utilize a non-reductionist approach to characterize the structural ensemble and dynamics of the full-length tumor suppressor p53, which contains both globular and disordered domains. An innovative, intein-based segmental isotope labeling strategy and advanced NMR methods will be utilized to characterize the conformational ensemble and dynamics of full-length p53, both free and in its complexes with specific and non-specific DNA targets. The disordered N- and C- terminal regions of p53 regulate DNA binding through dynamic intramolecular and intermolecular interactions that are modulated by constitutive and stress-induced posttranslational modifications. This research will provide new molecular level insights into the mechanisms by which this important tumor suppressor is dynamically regulated by the cascade of phosphorylation and acetylation that is triggered by genotoxic stress.


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	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	16	1/12/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $414,512 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	16	3/24/2021	NON-COMPETING CONTINUATION	$414,512
														Subtotal = $414,512

Issue Date FY: 2020 ( Subtotal = $414,512 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	15	3/9/2020	NON-COMPETING CONTINUATION	$414,512
														Subtotal = $414,512

Issue Date FY: 2019 ( Subtotal = $414,512 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	14	4/1/2019	NON-COMPETING CONTINUATION	$414,512
2019	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	12	2/10/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $414,512

Issue Date FY: 2018 ( Subtotal = $414,512 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	13	3/27/2018	COMPETING CONTINUATION	$414,512
														Subtotal = $414,512

Issue Date FY: 2017 ( Subtotal = $400,360 )
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	12	8/4/2017	NON-COMPETING CONTINUATION	$40,037
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	12	3/8/2017	NON-COMPETING CONTINUATION	$360,323
														Subtotal = $400,360

Issue Date FY: 2016 ( Subtotal = $400,360 )
2016	2016	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	11	3/3/2016	NON-COMPETING CONTINUATION	$394,120
2016	2016	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	11	4/30/2016	NON-COMPETING CONTINUATION	$6,240
														Subtotal = $400,360

Issue Date FY: 2015 ( Subtotal = $394,120 )
2015	2015	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	10	3/18/2015	NON-COMPETING CONTINUATION	$394,120
														Subtotal = $394,120

Issue Date FY: 2014 ( Subtotal = $394,120 )
2014	2014	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	9	3/26/2014	COMPETING CONTINUATION	$394,120
														Subtotal = $394,120

Issue Date FY: 2013 ( Subtotal = $369,805 )
2013	2013	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	8	6/17/2013	NON-COMPETING CONTINUATION	$24,909
2013	2013	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	8	3/25/2013	NON-COMPETING CONTINUATION	$344,896
														Subtotal = $369,805

Issue Date FY: 2012 ( Subtotal = $383,218 )
2012	2012	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	7	4/5/2012	NON-COMPETING CONTINUATION	$383,218
														Subtotal = $383,218

Issue Date FY: 2011 ( Subtotal = $383,218 )
2011	2011	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	6	3/21/2011	NON-COMPETING CONTINUATION	$348,379
2011	2011	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	6	6/13/2011	NON-COMPETING CONTINUATION	$34,839
														Subtotal = $383,218

Issue Date FY: 2010 ( Subtotal = $419,381 )
2010	2010	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	5	3/22/2010	COMPETING CONTINUATION	$387,088
2010	2009	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	4	3/22/2010	NON-COMPETING CONTINUATION	$0
2010	2009	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	002	4	3/22/2010	NON-COMPETING CONTINUATION	$32,293
														Subtotal = $419,381

Issue Date FY: 2009 ( Subtotal = $322,929 )
2009	2009	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	3/3/2009	NON-COMPETING CONTINUATION	$290,636
2009	2009	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	4	6/9/2009	NON-COMPETING CONTINUATION	$32,293
														Subtotal = $322,929

Issue Date FY: 2008 ( Subtotal = $322,929 )
2008	2008	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	3	3/21/2008	NON-COMPETING CONTINUATION	$322,929
														Subtotal = $322,929

Issue Date FY: 2007 ( Subtotal = $316,794 )
2007	2007	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	3/12/2007	NON-COMPETING CONTINUATION	$316,794
														Subtotal = $316,794

Issue Date FY: 2006 ( Subtotal = $326,255 )
2006	2006	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	3/30/2006	NEW	$326,255
														Subtotal = $326,255

Grand Total All Awards = $6,091,537

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Dynamic modulation of p53 activity by its disordered regulatory domains

Award Number: R01GM075995

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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