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Insights into Structure-Function Relationships of Matrix Metalloproteinase-1 from Computational and Experimental Studies

Award Number: R15GM132873
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Changes in the activity of collagenolytic matrix metalloproteinase-1 (MMP-1) have been linked to the progression of breast and lung cancer, leukemia, and melanoma. A complete understanding of MMP-1’s structure, mechanism, and function will aid the development of specific inhibitors of MMP-1 for treating diseases that have significant societal impact. The overarching goal of the proposed research is to provide the missing knowledge about conformational and mechanistic aspects of structure-function relationships in MMP-1 and to explain the effects of disease-related mutations in triple-helical peptide (THP) collagen models and MMP-1 at an atomistic level. The central hypothesis, supported by preliminary studies, is that MMP-1 collagenolysis critically relies on complex conformational changes that involve the enzyme's main structural elements and the THP. We further hypothesize that long-range correlated interactions with remote residues can control the catalytic mechanism of MMP-1. The goal of the proposed research application will be accomplished by two specific aims: Aim 1: What is the mechanism of product release after collagenolysis of the THP’s leading (L) chain? The study will determine the structural changes and energetics associated with the release of the product of the collagenolysis of the L chain of THP. Aim 2: What is the catalytic mechanism of collagenolysis of THP’s middle (M) and trailing (T) chains? The goal of Aim 2 is to model the catalytic mechanism of THP’s middle (M) and trailing (T) chains collagenolysis by means of combined quantum mechanics/molecular mechanics (QM/MM) methods and to validate the model using experimental measurements. The research adopts a novel approach by integrating state-of-the-art multilevel molecular modeling approaches in synergistic combination with experimental methods., thus offering unique opportunities for training undergraduate students in promising directions of biomedical research.


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	2023	MICHIGAN TECHNOLOGICAL UNIVERSITY	1400 TOWNSEND DR	HOUGHTON	MI	49931	HOUGHTON	USA	Biomedical Research and Research Training	001	2	1/17/2024	COMPETING CONTINUATION	$2,437
2024	2020	MICHIGAN TECHNOLOGICAL UNIVERSITY	1400 TOWNSEND DR	HOUGHTON	MI	49931	HOUGHTON	USA	Biomedical Research and Research Training	000	1	1/17/2024	NEW	-$2,437
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $427,001 )
2023	2023	MICHIGAN TECHNOLOGICAL UNIVERSITY	1400 TOWNSEND DR	HOUGHTON	MI	49931	HOUGHTON	USA	Biomedical Research and Research Training	001	2	6/20/2023	COMPETING CONTINUATION	$427,001
2023	2020	MICHIGAN TECHNOLOGICAL UNIVERSITY	1400 TOWNSEND DR	HOUGHTON	MI	49931	HOUGHTON	USA	Biomedical Research and Research Training	000	1	6/20/2023	NEW	$0
														Subtotal = $427,001

Issue Date FY: 2020 ( Subtotal = $439,609 )
2020	2020	MICHIGAN TECHNOLOGICAL UNIVERSITY	1400 TOWNSEND DR	HOUGHTON	MI	49931	HOUGHTON	USA	Biomedical Research and Research Training	000	1	3/3/2020	NEW	$458,788
2020	2020	MICHIGAN TECHNOLOGICAL UNIVERSITY	1400 TOWNSEND DR	HOUGHTON	MI	49931	HOUGHTON	USA	Biomedical Research and Research Training	001	1	3/17/2020	NEW	-$19,179
														Subtotal = $439,609

Grand Total All Awards = $866,610

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Insights into Structure-Function Relationships of Matrix Metalloproteinase-1 from Computational and Experimental Studies

Award Number: R15GM132873

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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