Substrate Specificity Determinants in Cancer-related Solute Carrier Transporters

癌症相关溶质载体转运蛋白的底物特异性决定因素

• 批准号: 8613172
• 负责人: Avner Schlessinger
• 金额: $ 32.78万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8613172
• 关键词: Affinity; Ally; Amino Acid Transporter; Antineoplastic Agents; Binding; Biochemical Pathway; Biological; Biological Assay; Biomass; Cell Line; Cell Proliferation; Cell membrane; Cells; Chemicals; Code; Complex; Data; Databases; Drug Prescriptions; Drug Targeting; Essential Amino Acids; Family; Genetic Variation; Glioblastoma; Glioma; Glucose Transporter; Goals; Health; Human; Individual; Laboratories; Life; Ligand Binding; Ligands; Malignant Neoplasms; Manuals; Maps; Mediating; Membrane; Membrane Proteins; Membrane Transport Proteins; Metabolic Pathway; Metabolism; Methods; Modeling; Molecular; Movement; Mutation; Normal Cell; Nutrient; Organelles; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Play; Point Mutation; Process; Proteins; Role; SLC2A1 gene; Side; Signaling Molecule; Single Nucleotide Polymorphism; Site; Specificity; Structural Models; Structure; Substrate Specificity; Testing; Toxin; Universities; Validation; Variant; Work; base; cancer cell; cell transformation; comparative; design; molecular dynamics; neoplastic cell; novel; programs; public health relevance; rapid growth; research study; screening; small molecule; solute; tool; tumor metabolism; uptake; virtual

SUMMARY Alterations in cell metabolism support rapid growth and proliferation of cells - key hallmarks of cancer. Solute Carrier (SLC) transporters are membrane proteins that mediate the movement of solutes such as metabolites and drugs across membranes, and can also function cooperatively in cancer metabolism pathways. For exam- ple, the amino acid transporters LAT-1 and ASCT2 are highly upregulated in glioma, where they play a key role in supplying growing tumor cells with essential amino acids that are used as nutrients to build biomass and signaling molecules to enhance proliferation. Our broad goal is to understand cancer mechanisms, by de- scribing the substrate specificity determinants in selected cancer-related transporter families via an integrated experimental and computational approach. First, we will identify novel ligands including endogenous metabolites and prescription drugs for three cancer- related SLC transporters (i.e., GLUT1, ASCT2, and LAT-1), using comparative modeling, virtual screening, and chemoinformatics methods, followed by experimental validation (performed by collaborators). The results obtained in this Aim will reveal unknown functions of the transporters and provide novel chemical tools to further characterize their functions. Second, we will define rules for substrate specificity of structurally related transporters, using structural comparison methods and analysis of the predicted transporter-ligand complexes. The specificity determinants will be used to rationalize and predict the impact of genetic variation on trans- porter function. Third, we will develop methods to rationally design polypharmacological ligands for transport- ers in cancer-metabolism pathways and examine the anti-proliferative effect of the discovered ligands on glioblastoma multiforme (GBM) cell lines. We will further establish the role of the transporters and their ligands in cancer, by predicting previously unknown protein-small molecule interactions via chemical similarity methods. Finally, based on our results, we will rationalize differences and commonalities between metabolic pathways of normal and transformed cells. Characterizing the interactions between key membrane transporters and their small molecule ligands will con- tribute to our understanding of how solutes get transported across the membranes of cells and organelles, which is essential for many of life's processes. Furthermore, describing substrate specificity in proteins im- portant for cancer metabolism will provide chemical tools that would allow us to understand how perturbed metabolic networks are related to cancer and to discover novel leads for designing small molecules with opti- mized affinities against novel cancer drug targets. Ultimately, the results obtained in our studies can be a sig- nificant step toward designing cancer drugs.

摘要 细胞代谢的改变支持细胞的快速生长和增殖--这是癌症的关键特征。溶质 载体(SLC)转运蛋白是一种膜蛋白，它调节诸如代谢物之类的溶质的运动 和药物跨膜，也可以在癌症代谢途径中协同发挥作用。为了考试- PLE，氨基酸转运蛋白LAT-1和ASCT2在胶质瘤中高度上调，在胶质瘤中发挥关键作用 在为生长中的肿瘤细胞提供必需氨基酸的过程中，这些必需氨基酸被用作构建生物量和 促进增殖的信号分子。我们的广泛目标是了解癌症的机制，通过去... 在选定的癌症相关转运蛋白家族中通过一种 综合实验和计算方法。 首先，我们将确定新的配体，包括内源性代谢物和治疗三种癌症的处方药- 相关的SLC转运体(即GLUT1、ASCT2和LAT-1)，使用比较建模、虚拟筛选和 化学信息学方法，然后是实验验证(由合作者执行)。结果是 这一目标的获得将揭示转运蛋白未知的功能，并提供新的化学工具 进一步描述它们的功能。其次，我们将定义结构相关的底物专一性的规则 转运体，使用结构比较方法和分析预测的转运体-配体复合体。 特异性决定因素将被用来合理化和预测遗传变异对反式病毒的影响。 搬运工功能。第三，我们将开发合理设计用于运输的多药物配体的方法- ERs在肿瘤代谢途径中的作用，并检测已发现的配体对肿瘤细胞增殖的抑制作用 多形性胶质母细胞瘤(GBM)细胞系。我们将进一步确定转运体及其配体的作用 在癌症中，通过化学相似性预测以前未知的蛋白质-小分子相互作用 方法：研究方法。最后，根据我们的结果，我们将合理解释新陈代谢之间的差异和共同点。 正常细胞和转化细胞的通路。 表征关键的膜转运蛋白与它们的小分子配体之间的相互作用将有助于... 这归功于我们对溶质如何通过细胞膜和细胞器进行运输的理解， 这对生命的许多过程都是必不可少的。此外，描述蛋白质免疫的底物特异性。 癌症新陈代谢的重要性将提供化学工具，使我们能够了解 代谢网络与癌症有关，并为设计具有最佳选择的小分子寻找新的线索。 针对新的抗癌药物靶点的美化亲和力。归根结底，我们的研究结果可能是一个信号- 朝着设计抗癌药物迈出了重要的一步。