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Understanding the Ligand Binding by Non-Heme Fe(II)- and 2-Oxoglutarate-Dependent Histone Demethylases

Award Number: R15GM139118
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Understanding the Ligand Binding by Non-Heme Fe(II)- and 2-Oxoglutarate-Dependent Histone Demethylases - PROJECT SUMMARY One of the most important tools in epigenetic regulation is through demethylation of histone proteins. The most abundant histone demethylases belong to non-heme iron and 2- oxoglutarate- (2OG) dependent JmjC- subfamily that catalyze the demethylation of Nε-methyllysine residues in histone proteins. KDM4A and KDM7B are Fe (II) and 2OG-dependant histone lysine demethylase that have been linked to various forms of cancer such as prostate cancer, breast cancer, laryngeal, gastric and endometrial carcinoma. The current proposal combines multiscale computational methods with advanced spectroscopic techniques to elucidate the differences at atomistic and electronic structural levels between two non-heme Fe (II) and 2-oxoglutarate (2OG)-dependent histone demethylases (KDMs): KDM4A and KDM7B in respect to: i) the binding of co-substrates - 2OG, H3 histone and dioxygen; and ii) the long-range correlated motions between the binding site, second sphere and more distant protein regions that are in crucial importance for the binding process. This gap in our knowledge base cannot be resolved through either experimental or computational approaches in isolation. The proposed research will inform on the atomistic aspects of the preference of KDM4A for tri- methylated lysine residues and of KDM7B towards di- and mono-methylated lysines. The study will elucidate why KDM4A is able to bind and demethylate arginine residues in contrast to KDM7B. This research will close the knowledge gap about how altered protein environments in the two KDMs selectively stabilize the important species along the formation of the complete catalytically productive enzyme-substrate complex. The research will also identify specific long-range correlated motions of key binding residues with a second sphere residues and longer-distant protein regions. Such correlated interactions are expected to be enzyme-selective which will provide novel opportunities for the design of enzyme-selective epigenetic drugs. An exciting aspect of the research plan is that it will provide motivated undergraduate students with a unique opportunity to engage in top class research using modern computational and experimental methods in line with the mission of the Academic Research Enhancement Award.


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 = $0 )
2025	2021	MICHIGAN TECHNOLOGICAL UNIVERSITY	1400 TOWNSEND DR	HOUGHTON	MI	49931	HOUGHTON	USA	Biomedical Research and Research Training	000	1	4/10/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $403,453 )
2024	2024	MICHIGAN TECHNOLOGICAL UNIVERSITY	1400 TOWNSEND DR	HOUGHTON	MI	49931	HOUGHTON	USA	Biomedical Research and Research Training	002	2	7/11/2024	COMPETING CONTINUATION	$403,453
2024	2021	MICHIGAN TECHNOLOGICAL UNIVERSITY	1400 TOWNSEND DR	HOUGHTON	MI	49931	HOUGHTON	USA	Biomedical Research and Research Training	001	1	7/11/2024	NEW	$0
2024	2021	MICHIGAN TECHNOLOGICAL UNIVERSITY	1400 TOWNSEND DR	HOUGHTON	MI	49931	HOUGHTON	USA	Biomedical Research and Research Training	000	1	5/6/2024	NEW	$0
														Subtotal = $403,453

Issue Date FY: 2021 ( Subtotal = $382,448 )
2021	2021	MICHIGAN TECHNOLOGICAL UNIVERSITY	1400 TOWNSEND DR	HOUGHTON	MI	49931	HOUGHTON	USA	Biomedical Research and Research Training	000	1	5/31/2021	NEW	$382,448
														Subtotal = $382,448

Grand Total All Awards = $785,901

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Understanding the Ligand Binding by Non-Heme Fe(II)- and 2-Oxoglutarate-Dependent Histone Demethylases

Award Number: R15GM139118

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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