Thursday, January 1, 2026 1/1/2026

Linking Conformational Dynamics to Activity Impairment of Disease-associated Human Enzymes

Award Number: R35GM160337
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: 09/01/2025
PERIOD OF PERFORMANCE END DATE: 08/31/2030

Group Awards By:

View Award Description

Linking Conformational Dynamics to Activity Impairment of Disease-associated Human Enzymes - Project Summary/Abstract Motions through a complicated conformational landscape are almost certainly central to enzyme activity. This project aims to test the hypothesis that residue replacements distant from the active site impair activity in human disease-associated missense variants by altering protein dynamics. These proof-of-concept studies will use asparagine synthetase (ASNS) and its variants linked to asparagine synthetase deficiency (ASNSD) as a model system. Leveraging my expertise in mechanistic enzymology, protein dynamics, and the development of high- throughput screening assays, we will combine enzyme kinetics, hydrogen-deuterium exchange mass spectrometry (HDX-MS), and cell-based assays to correlate changes in conformational dynamics with the altered catalytic activities seen for two representative ASNSD-associated variants (ASNSDVs). Time- and temperature- dependent HDX-MS will be used to place the dynamic differences between the wild-type ASNS and the ASNSDVs on a quantitative basis. A cell-based functional complementation assay will also allow us to examine how hydrophobic residue networks permit distal residue changes to affect individual steps in complicated kinetic mechanisms. Project outcomes will clarify how missense mutations that are distal to the enzyme active site lead to activity impairment and will lay a strong foundation for applying this general approach to understand 1,500 human enzymes linked to 2,500 inherited diseases.


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 = $417,498 )
2025	2025	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	1	8/19/2025	NEW	$417,498
														Subtotal = $417,498

Grand Total All Awards = $417,498

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Linking Conformational Dynamics to Activity Impairment of Disease-associated Human Enzymes

Award Number: R35GM160337

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: 09/01/2025

PERIOD OF PERFORMANCE END DATE: 08/31/2030

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer