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Investigating the relationship between allostery and substrate specificity in protein tyrosine phosphatases

Award Number: R01GM112781
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: 01/01/2015
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Investigating the relationship between allostery and substrate specificity in protein tyrosine phosphatases - Protein tyrosine phosphatases (PTPs) are enzymes that regulate an enormous number of biological processes through the modulation of their target proteins (substrates). PTPs do this by catalyzing the removal of a phosphate group from the amino acid tyrosine in their targets, which alters the activity of the target enzyme. The misregulation of PTPs are linked to a number of diseases including type II diabetes, obesity, cancer, and inflammation and therefore PTPs are viewed as potential drug targets. A primary obstacle to drugging PTPs is that the sites of their enzymatic action (active sites) are nearly identical, thus targeting a specific PTP enzyme by a drug focused on the active site has not been a productive endeavor. A solution to the problem is to target the drug to sites on PTPs that are distant from the active site, the so-called allosteric sites, which are not identical across the family of PTPs. A difficulty with this approach is the challenge of identification and characterization of these allosteric sites to obtain a better understanding of how they interact, from long molecular distances, with the active site. We hypothesize that different substrates alter the protein structure in a distinct manner and cause different allosteric sites to be exposed. We plan to test this hypothesis and characterize these allosteric sites through a powerful combination of solution nuclear magnetic resonance (NMR) spectroscopy, biochemical, and computational approaches in two medically important human enzymes, protein tyrosine phosphatase 1B (PTP1B) and Vaccinia H1-related (VHR) phosphatase. Our aims are: To identify and characterize substrate dependent allosteric sites in PTP1B and VHR using different substrate peptides from the natural in vivo targets of these PTPs. We will identify these sites by monitoring changes in NMR chemical shift and dynamics parameters. In complementary experiments we will use novel computational methods developed by our research team to further understand the mechanism of allostery in these enzymes. Subsequently we will validate our newly identified allosteric sites by mutation followed by functional assays and computational methods to better understand the impact of the allosteric sites on the substrate specific enzymatic activity in PTP1B and VHR.


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 = $388,380 )
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	8	11/15/2023	NON-COMPETING CONTINUATION	$349,542
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	8	6/17/2024	NON-COMPETING CONTINUATION	$38,838
														Subtotal = $388,380

Issue Date FY: 2023 ( Subtotal = $387,226 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	7	2/16/2023	NON-COMPETING CONTINUATION	$38,723
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	7	12/13/2022	NON-COMPETING CONTINUATION	$348,503
														Subtotal = $387,226

Issue Date FY: 2022 ( Subtotal = $386,123 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	6	6/27/2022	NON-COMPETING CONTINUATION	$38,612
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	6	11/24/2021	NON-COMPETING CONTINUATION	$347,511
														Subtotal = $386,123

Issue Date FY: 2021 ( Subtotal = $385,067 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	5	1/29/2021	COMPETING CONTINUATION	$385,067
														Subtotal = $385,067

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	4	7/23/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	4	2/8/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $323,227 )
2018	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	4	12/18/2017	NON-COMPETING CONTINUATION	$290,903
2018	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	4	5/9/2018	NON-COMPETING CONTINUATION	$32,324
														Subtotal = $323,227

Issue Date FY: 2017 ( Subtotal = $323,059 )
2017	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	3	8/8/2017	NON-COMPETING CONTINUATION	$32,306
2017	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	3	12/14/2016	NON-COMPETING CONTINUATION	$290,753
														Subtotal = $323,059

Issue Date FY: 2016 ( Subtotal = $323,308 )
2016	2016	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	2	2/22/2016	NON-COMPETING CONTINUATION	$32,332
2016	2016	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	2	12/2/2015	NON-COMPETING CONTINUATION	$290,976
														Subtotal = $323,308

Issue Date FY: 2015 ( Subtotal = $306,000 )
2015	2015	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	1	12/30/2014	NEW	$306,000
														Subtotal = $306,000

Grand Total All Awards = $2,822,390

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Investigating the relationship between allostery and substrate specificity in protein tyrosine phosphatases

Award Number: R01GM112781

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: 01/01/2015

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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