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A comprehensive thermodynamic and structural characterization of ion channel function and its regulation by the lipid bilayer composition

Award Number: R35GM149523
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 The central tenet of this grant application contains two interdependent components 1) how does the structure determine the function of K+-channels? and how does the cell membrane phospholipid composition regulate their structure-function correlations? Our work deal with these two fundamental questions, which encompasses three aspects of ion channel physiology: 1) Which are the structural changes underlying K+- channel gating, permeation, and selectivity? 2) How does a bidirectional allosteric coupling between the activation gate (AG) and the selectivity filter (SF) control K+-channels function? and 3) How does the cell membrane lipid composition regulate K+-channels behavior? Understanding at the atomic level how K+- channels work will assist during the discovery of novel therapeutic drugs. We will use several methodological advancements developed by us during the last 10 years of continuous funding from the NIH. These achievements are: 1) the elucidation of an atomic resolution gating cycle of a K+-channel 2) the engineering of a disulfide bridged locked open KcsA scaffold that produces atomic resolution diffracting crystals and allow us to characterize its function by electrophysiology at pH 7.0 (a physiologically relevant pH) 3) the measuring of the alkali metal ions binding affinity by Isothermal Titration Calorimetry of the whole selectivity filter of a K+-channel in the open conformation and/or of individual ion binding sites 4) the discovery of a novel mechanism of KcsA activation by reducing the thickness of the cell membrane and 5) the development of a new methodology for the overexpression of properly folded and functional Human K+-channels of Biomedical Importance in E. coli cells. Our work using KcsA as a structural surrogate is foundational of our current understanding of K+-channel function. Now we are expanding into human K+-channels by developing a groundbreaking new methodology for the overexpression of properly folded and functional human Kv-channels in E. coli cells, which eliminates the otherwise time consuming and outrageously expensive use of eukaryotic cells. We will develop an integrative understanding of how the structure of ion channels change its conformation to regulate their function within an energetic landscape determined by the lipid composition of the cell membrane. We aim to determine the structural changes underlying ion permeation, ion selectivity and C-type inactivation gating and their interdependence with the lipid bilayer composition of the cell membrane in a bacterial channel and in two human Kv-channels of Biomedical Relevance. Finally, we will produce a conceptual framework about how the allosteric coupling between a K+-channel’s selectivity filter and its activation gate define ion channel function and how is modulated by subunit cooperativity and the phospholipid composition of the cell membrane. The completion of this grant application will produce invaluable information to assist in the smart design of safer therapeutic drugs.


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 = $344,250 )
2024	2024	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Biomedical Research and Research Training	000	2	1/17/2024	NON-COMPETING CONTINUATION	$344,250
														Subtotal = $344,250

Issue Date FY: 2023 ( Subtotal = $593,975 )
2023	2023	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Biomedical Research and Research Training	000	1	3/14/2023	NEW	$593,975
														Subtotal = $593,975

Grand Total All Awards = $938,225

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A comprehensive thermodynamic and structural characterization of ion channel function and its regulation by the lipid bilayer composition

Award Number: R35GM149523

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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