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Substrate Specificity Determinants in Nutrient Solute Carrier Transporters

Award Number: R01GM108911
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: 04/01/2014
PERIOD OF PERFORMANCE END DATE: 04/30/2023

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Substrate Specificity Determinants in Nutrient Solute Carrier Transporters - SUMMARY In humans, there are over 460 Solute Carrier (SLC) transporters that mediate the import and efflux of solutes, including neurotransmitters, nutrients, and ions. The SLCs are emerging as key therapeutic targets for a variety of diseases and disorders. For example, nutrient SLC transporters play a major role in reprogrammed metabolic networks in cancer, autoimmune disease, and heart ischemia, by supplying cells with nutrients that are used to build biomass or serve as signaling molecules that enhance cell proliferation and differentiation, or regulate cell death. Our broad goal is to describe the substrate and inhibitor specificity determinants in nutrient transporters and develop novel strategies to modulate their functions. We take an integrative approach that includes computational biology and organic chemistry, coupled with biochemical and biophysical approaches, and in vitro models of disease, to characterize the Alanine-Serine-Cysteine Transporter 2 (ASCT2, SLC1A5). In Aim 1 of this project, we will generate and refine homology models for the human SLC1 family in multiple conformations. We will describe structural features of the models’ substrate binding site and recently discovered allosteric site(s), that determine substrate and inhibitor specificity. Key residues will be tested with site-directed mutagenesis and electrophysiological approaches. Finally, we will develop a publicly-accessible database that includes homology models for all modelable human SLC transporters, and maps disease-related mutations onto the models and provides their predicted functional effect. In Aim 2, we will rationally design small molecule tool compounds that modulate the function of nutrient transporters via distinct mechanisms. This will expand the chemical space of transporter inhibitors and provide a test for the models developed in Aim 1. We will focus on the following approaches: (A) optimizing and characterizing novel conformation-specific inhibitors, such as photoactivatable and fluorescent compounds that interact with the substrate binding site of ASCT2; (B) designing allosteric inhibitors targeting the domain-domain interface in ASCT2, to test the putative elevator mechanism of this transporter; and (C) developing inhibitors with dual specificity for ASCT2 and the L-type Amino Acid Transporter 1 (LAT1, SLC7A5), which we hypothesize to have a pronounced inhibitory effect on cell proliferation due to their cooperativity in reprogrammed metabolic networks. If successful, this project will improve our understanding of structure-function relationships in emerging therapeutic targets. This project will also provide novel chemical probes to further characterize the structure of these proteins and their role in disease, as well as a useful publicly available online resource.


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	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	9	2/14/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $376,866 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	9	4/27/2022	NON-COMPETING CONTINUATION	$376,866
														Subtotal = $376,866

Issue Date FY: 2021 ( Subtotal = $376,866 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	8	4/1/2021	NON-COMPETING CONTINUATION	$376,866
														Subtotal = $376,866

Issue Date FY: 2020 ( Subtotal = $376,866 )
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	7	5/6/2020	NON-COMPETING CONTINUATION	$376,866
														Subtotal = $376,866

Issue Date FY: 2019 ( Subtotal = $398,055 )
2019	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	6	6/20/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$398,055
2019	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	001	5	7/22/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $398,055

Issue Date FY: 2018 ( Subtotal = $314,747 )
2018	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	5	3/21/2018	NON-COMPETING CONTINUATION	$283,272
2018	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	001	5	5/15/2018	NON-COMPETING CONTINUATION	$31,475
														Subtotal = $314,747

Issue Date FY: 2017 ( Subtotal = $314,747 )
2017	2017	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	4	3/17/2017	NON-COMPETING CONTINUATION	$283,272
2017	2017	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	001	4	6/20/2017	NON-COMPETING CONTINUATION	$31,475
														Subtotal = $314,747

Issue Date FY: 2016 ( Subtotal = $314,747 )
2016	2016	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Biomedical Research and Research Training	000	3	3/21/2016	NON-COMPETING CONTINUATION	$314,747
														Subtotal = $314,747

Issue Date FY: 2015 ( Subtotal = $314,747 )
2015	2015	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Biomedical Research and Research Training	000	2	4/21/2015	NON-COMPETING CONTINUATION	$314,747
														Subtotal = $314,747

Issue Date FY: 2014 ( Subtotal = $327,786 )
2014	2014	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Biomedical Research and Research Training	000	1	3/25/2014	NEW	$327,786
														Subtotal = $327,786

Grand Total All Awards = $3,115,427

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Substrate Specificity Determinants in Nutrient Solute Carrier Transporters

Award Number: R01GM108911

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: 04/01/2014

PERIOD OF PERFORMANCE END DATE: 04/30/2023

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