Structural basis for differential regulation and selective inhibition of human CTP synthase 1

人CTP合酶1差异调节和选择性抑制的结构基础

基本信息

批准号：
10393643
负责人：
Justin M Kollman
金额：
$ 48.94万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-16 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10393643
关键词：
Active Sites Adopted Affinity Anabolism Autoimmune Diseases B Cell Proliferation Binding Binding Sites Biochemical Biological Assay Biophysics Bypass C-terminal Cell Proliferation Cells Cellular Assay Chemicals Complex Cryoelectron Microscopy DNA biosynthesis Defect Dependence Development Disease Dissection Drug Targeting Enzyme Inhibitor Drugs Enzymes Failure Feedback Genes Growth Human Hyperactivity Immune response Immune system Immunologic Deficiency Syndromes Immunosuppression Immunosuppressive Agents Impairment Inherited Learning Leukocytes Lymphocyte Count Metabolism Molecular Molecular Conformation Mutagenesis Nucleotide Biosynthesis Nucleotides Pathway interactions Peptides Pharmaceutical Preparations Phosphorylation Physiological Play Production Protein Isoforms Pyrimidine Nucleotides RNA chemical synthesis Regulation Reporting Resolution Ribonucleotides Role Solid Specificity Structure T-Lymphocyte Tail Testing Therapeutic immunosuppression Tissues Work base biophysical properties design drug development flexibility human tissue improved in vitro activity inhibitor insight loss of function mutation lymphocyte proliferation membrane synthesis novel novel therapeutics organ transplant rejection pathogen prevent scaffold side effect small molecule inhibitor success therapeutic development tool uptake

Active Sites Adopted Affinity Anabolism Autoimmune Diseases B Cell Proliferation Binding Binding Sites Biochemical Biological Assay Biophysics Bypass C-terminal Cell Proliferation Cells Cellular Assay Chemicals Complex Cryoelectron Microscopy DNA biosynthesis Defect Dependence Development Disease Dissection Drug Targeting Enzyme Inhibitor Drugs Enzymes Failure Feedback Genes Growth Human Hyperactivity Immune response Immune system Immunologic Deficiency Syndromes Immunosuppression Immunosuppressive Agents Impairment Inherited Learning Leukocytes Lymphocyte Count Metabolism Molecular Molecular Conformation Mutagenesis Nucleotide Biosynthesis Nucleotides Pathway interactions Peptides Pharmaceutical Preparations Phosphorylation Physiological Play Production Protein Isoforms Pyrimidine Nucleotides RNA chemical synthesis Regulation Reporting Resolution Ribonucleotides Role Solid Specificity Structure T-Lymphocyte Tail Testing Therapeutic immunosuppression Tissues Work base biophysical properties design drug development flexibility human tissue improved in vitro activity inhibitor insight loss of function mutation lymphocyte proliferation membrane synthesis novel novel therapeutics organ transplant rejection pathogen prevent scaffold side effect small molecule inhibitor success therapeutic development tool uptake

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项目摘要

PROJECT SUMMARY Cellular proliferation increases demand for ribonucleotide pools to provide precursors for increased RNA, DNA, and membrane synthesis. This demand exceeds the capacity of uptake and salvage pathways, and must be met by increased de novo biosynthesis. In particular, lymphocyte proliferation is dependent on increased nucleotide levels, and targeting nucleotide biosynthesis pathways is the basis for a number of highly successful immunosuppressive treatments. CTP Synthase (CTPS) is the key regulatory enzyme in pyrimidine nucleotide biosynthesis. Humans have two CTPS isoforms encoded on separate genes, CTPS1 and CTPS2. While CTPS1 expression is generally increased in proliferative tissues, little else is known about differential roles of the two isoforms or how they are regulated. CTPS1 plays a critical role in the immune response, and loss of function mutations in humans cause severe immunodeficiency. Loss of CTPS1 results in impaired T and B-cell proliferation, but does not have deleterious effects in other human tissues, indicating unique dependence of the immune response on CTPS1 function. Selective inhibition of CTPS1, therefore, is considered a potentially powerful approach to immunosuppressive therapies with limited off-target effects. A number of inhibitors that specifically target CTPS1 have recently been reported, but the mechanisms of inhibition remain unclear. Here, we focus on the structural and functional characterization of CTPS1 and CTPS2 regulation by native allosteric regulators and by selective small molecule inhibitors. This work will provide insight into the control of nucleotide biosynthesis during cellular proliferation, and serve as the basis for design and targeted discovery of novel compounds with potential for immunosuppressive therapies.

项目摘要细胞增殖增加了对核糖核苷酸池的需求，以提供增加RNA，DNA，，和膜合成。这种需求超过了吸收和打捞途径的能力，必须是通过从头生物合成增加而满足。特别是，淋巴细胞增殖取决于增加核苷酸水平和靶向核苷酸生物合成途径是许多高度成功的基础免疫抑制治疗。 CTP合酶（CTP）是嘧啶核苷酸中的关键调节酶生物合成。人类在单独的基因CTPS1和CTPS2上编码了两个CTPS同工型。尽管在增殖组织中，CTPS1表达通常增加，关于两种同工型或如何调节它们。 CTPS1在免疫反应中起着至关重要的作用，丧失人类的功能突变会导致严重的免疫缺陷。 CTPS1的丢失导致T和B细胞受损扩散，但在其他人体组织中没有有害作用，表明 CTPS1功能的免疫反应。因此，选择性抑制CTPS1被认为是潜在的有限的脱靶效果的免疫抑制疗法的强大方法。许多抑制剂最近已经报道了特定目标CTPS1，但抑制机制尚不清楚。这里，我们专注于CTPS1和CTPS2调节的结构和功能表征调节剂和选择性小分子抑制剂。这项工作将为核苷酸的控制提供洞察力细胞增殖期间的生物合成，并作为设计和靶向发现的基础具有免疫抑制疗法潜力的化合物。