权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Substrate Specificity Determinants in Nutrient Solute Carrier Transporters

营养溶质载体转运蛋白的底物特异性决定因素

基本信息

批准号：
10735432
负责人：
Avner Schlessinger
金额：
$ 43.78万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-10 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735432
关键词：
Alanine Allosteric Site Amino Acid Transporter Amino Acids Antiviral Agents Autoimmune Diseases Basic Amino Acid Transport Systems Binding Binding Sites Biochemical Biochemical Pathway Biological Biological Assay Biology Biomass Biophysics Cancer cell line Cell Death Cell Differentiation process Cell Line Cell Proliferation Cells Cellular Metabolic Process Chemicals Collaborations Computing Methodologies Coupled Cryoelectron Microscopy Cysteine Data Development Diabetes Mellitus Disease Docking Drug Delivery Systems Drug Design Drug Targeting Electrophysiology (science)Electrostatics Family Free Energy Future Glutamine Goals Grant Health Human Hydrophobicity Hyperactivity Ion Transport Ions Kinetics Knowledge Laboratories Leucine Libraries Ligands Malignant Neoplasms Malignant neoplasm of prostate Mediating Membrane Membrane Transport Proteins Metabolic Diseases Metabolism Methods Modeling Molecular Molecular Conformation Myocardial Ischemia Neurotransmitters Nutrient Organic Synthesis Pathology Pharmaceutical Preparations Pharmacology Physiological Play Prodrugs Proliferating Proteins Role Serine Shapes Signaling Molecule Site-Directed Mutagenesis Specificity Starvation Structural Models Structure Structure-Activity Relationship Substrate Specificity Sugar Acids Synthesis Chemistry T-Lymphocyte Testing Toxin Work amino acid metabolism analog biophysical techniques cancer cell cancer type computational chemistry design drug discovery inhibitor innovation melanoma neoplastic cell nervous system disorder novel novel strategies rapid growth rational design small molecule solute structural biology therapeutic target tool triple-negative invasive breast carcinoma uptake virtual

项目摘要

SUMMARY Alterations in cell metabolism support rapid growth and proliferation of cells in pathologies such as cancer, au- toimmune disease, and heart ischemia, resulting in increased reliance on the metabolism of amino acids such as glutamine and leucine. Nutrient Solute Carrier (SLC) transporters play a major role in reprogrammed meta- bolic networks by supplying cells with nutrients that are used to build biomass, serve as signaling molecules that enhance cell proliferation and differentiation, or regulate cell death. Our broad goal is to describe the sub- strate and inhibitor specificity determinants in disease-related nutrient SLC transporters and develop unique strategies to modulate their functions. We take an integrative approach that includes computational chemistry methods, coupled with biochemical and biophysical approaches and disease-related cell lines, to char- acterize two amino acid transporters that play a key role in metabolism of rapidly-growing cells: the Alanine- Serine-Cysteine Transporter (SLC1A5, ASCT2), a Na+-dependent amino acid exchanger that modulates intra- cellular glutamine levels, and the Amino Acid Transporter B0+ (ATB0+, SLC6A14), a neutral and cationic amino acid transporter, driven by Na+ and Cl- co-transport. In Aim 1 of this project, we will continue characterizing ASCT2, a well-validated drug target for various patholo- gies (eg triple negative breast cancer and prostate cancer). Despite recent advancements in our understanding of ASCT2 structure and function made by us and others, many aspects of its biology are highly unexplored. We will rationally design chemical tools that modulate the activity of ASCT2 using unique mechanisms, including: (A) allosteric inhibitors interacting with a recently identified allosteric site; (B) covalent inhibitors targeting a unique cysteine residue in the substrate binding site of ASCT2; and (C) conformation-specific small molecule modulators targeting specific subpockets in the substrate binding site. In Aim 2, we will characterize SLC6A14, an understudied transporter involved in cancer and metabolic diseases. We will develop structural models of SLC6A14 in different conformations. We will describe biophysical features of the models’ substrate binding site, including electrostatic potential, size, shape, and hydrophobicity, to develop hypotheses for the substrate and inhibitor specificity determinants in SLC6A14. We will use this knowledge to guide the development of inhibitors and substrates, including photoactivatable compounds, to directly test inhibitor-binding site interaction(s). Successful completion of this project will provide a greater understanding of mechanisms of transport and inhi- bition of nutrient transporters, as well as novel chemical tools to further characterize their role in disease. Notably, we will test an emerging and innovative approach to transporter drug discovery that targets allosteric modulation and covalent inhibition via small molecules, to deprive hyper-proliferating cells of nutrients, potentially expanding future applications to treat other diseases that involve SLCs.

总结