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Structural Dynamics of Multi-drug Transporters

Award Number: R01GM077659
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Structural Dynamics of Multi-drug Transporters - Bacterial homeostasis and survival is critically dependent on defense mechanisms that modify, deactivate, or extrude cytotoxic molecules such as antiseptics and antibiotics, which passively cross the membrane down their concentration gradients. One ubiquitous and highly conserved mechanism entails the expression of polyspecific membrane transporters, referred to as multidrug (MDR) transporters, which harness the Gibbs energy stored in ion electrochemical gradients to power the uphill vectorial clearance of a broad spectrum of cytotoxic molecules. Energy-coupled isomerization of the transporter between multiple intermediates enables alternating access of the substrate binding site from one side of the membrane to the other. Defining the structural elements mediating alternating access and decoding the mechanism of energy conversion in a lipid bilayer-like environment are exciting frontiers in the field and critical for defining transport mechanisms. This proposal will continue support of a productive research program focused on addressing these questions for two families of ion-coupled MDR transporters that have been implicated in clinical drug resistance. Our approach capitalizes on the tool kit of EPR spectroscopy in the context of high resolution structures, is informed by functional studies, and is contextualized through collaborative molecular modeling efforts. Aim 1 seeks to elucidate principles of ion-substrate coupling, identify residues critical for ion and substrate binding, and reveal how specific transporter-lipids interactions shape the energy landscape of conformational changes in two archetypes of the Multidrug and Toxin Extrusion (MATE) family of multidrug transporters. Aim 2 seeks to identify conserved elements of alternating access and ion-substrate coupling for the major facilitator (MFS) family of MDR transporters. We will test a detailed mechanism of ligand-dependent conformational changes, developed in the previous funding period, that integrate ion coupling with specific lipid interactions in the context of a well-established transport model. Together, the two aims will illuminate mechanistic principles for families of transporters implicated in the phenomenon of drug resistance and basic bacterial defense strategies.


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 = -$2,153 )
2025	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	16	4/21/2025	NON-COMPETING CONTINUATION	-$2,153
														Subtotal = -$2,153

Issue Date FY: 2023 ( Subtotal = $235,769 )
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	16	3/23/2023	NON-COMPETING CONTINUATION	$235,769
														Subtotal = $235,769

Issue Date FY: 2022 ( Subtotal = $235,769 )
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	15	3/22/2022	NON-COMPETING CONTINUATION	$212,192
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	001	15	6/27/2022	NON-COMPETING CONTINUATION	$23,577
														Subtotal = $235,769

Issue Date FY: 2021 ( Subtotal = $297,583 )
2021	2021	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	001	14	4/29/2021	NON-COMPETING CONTINUATION	-$54,277
2021	2021	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	14	3/26/2021	NON-COMPETING CONTINUATION	$289,860
2021	2021	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	002	14	7/28/2021	SUPPLEMENT FOR EXPANSION	$62,000
														Subtotal = $297,583

Issue Date FY: 2020 ( Subtotal = $235,025 )
2020	2020	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	002	13	9/5/2020	COMPETING CONTINUATION	$5,748
2020	2020	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	13	4/14/2020	COMPETING CONTINUATION	$235,025
2020	2018	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	001	12	9/5/2020	NON-COMPETING CONTINUATION	-$5,748
														Subtotal = $235,025

Issue Date FY: 2018 ( Subtotal = $317,523 )
2018	2018	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	12	3/15/2018	NON-COMPETING CONTINUATION	$285,770
2018	2018	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	001	12	5/7/2018	NON-COMPETING CONTINUATION	$31,753
														Subtotal = $317,523

Issue Date FY: 2017 ( Subtotal = $317,523 )
2017	2017	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	001	11	8/18/2017	NON-COMPETING CONTINUATION	$31,753
2017	2017	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	11	3/28/2017	NON-COMPETING CONTINUATION	$285,770
														Subtotal = $317,523

Issue Date FY: 2016 ( Subtotal = $317,523 )
2016	2016	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	000	10	3/21/2016	NON-COMPETING CONTINUATION	$317,523
														Subtotal = $317,523

Issue Date FY: 2015 ( Subtotal = $317,523 )
2015	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	000	9	3/20/2015	COMPETING CONTINUATION	$317,523
														Subtotal = $317,523

Issue Date FY: 2013 ( Subtotal = $301,050 )
2013	2013	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	000	8	2/21/2013	NON-COMPETING CONTINUATION	$280,772
2013	2013	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	001	8	6/10/2013	NON-COMPETING CONTINUATION	$20,278
														Subtotal = $301,050

Issue Date FY: 2012 ( Subtotal = $311,969 )
2012	2012	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	000	7	3/16/2012	NON-COMPETING CONTINUATION	$311,969
														Subtotal = $311,969

Issue Date FY: 2011 ( Subtotal = $311,303 )
2011	2011	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	002	6	8/16/2011	NON-COMPETING CONTINUATION	$28,301
2011	2011	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	001	6	3/9/2011	NON-COMPETING CONTINUATION	-$53,690
2011	2011	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	000	6	1/31/2011	NON-COMPETING CONTINUATION	$336,692
														Subtotal = $311,303

Issue Date FY: 2010 ( Subtotal = $370,842 )
2010	2010	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	003	5	8/18/2010	SUPPLEMENT FOR EXPANSION	$29,721
2010	2010	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	002	5	3/12/2010	COMPETING CONTINUATION	$313,100
2010	2009	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	001	4	3/11/2010	NON-COMPETING CONTINUATION	$28,021
2010	2009	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	000	4	3/11/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $370,842

Issue Date FY: 2009 ( Subtotal = $445,549 )
2009	2009	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Trans-NIH Recovery Act Research Support	002	4	8/28/2009	SUPPLEMENT FOR EXPANSION	$165,338
2009	2009	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	000	4	2/23/2009	NON-COMPETING CONTINUATION	$252,190
2009	2009	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	001	4	6/9/2009	NON-COMPETING CONTINUATION	$28,021
														Subtotal = $445,549

Issue Date FY: 2008 ( Subtotal = $303,551 )
2008	2008	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	000	3	3/3/2008	NON-COMPETING CONTINUATION	$303,551
														Subtotal = $303,551

Issue Date FY: 2007 ( Subtotal = $432,305 )
2007	2007	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	001	2	8/27/2007	SUPPLEMENT FOR EXPANSION	$32,675
2007	2007	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	002	2	8/31/2007	SUPPLEMENT FOR EXPANSION	$97,520
2007	2007	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	000	2	3/1/2007	NON-COMPETING CONTINUATION	$302,110
														Subtotal = $432,305

Issue Date FY: 2006 ( Subtotal = $318,970 ) (Continued on the next page)
Grand Total All Awards = $5,067,624

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Structural Dynamics of Multi-drug Transporters

Award Number: R01GM077659

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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