Molecular mechanism of nucleobase/vitamin C transporters
核碱基/维生素C转运蛋白的分子机制
基本信息
- 批准号:9900837
- 负责人:
- 金额:$ 35.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-06-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAffectAnemiaAnionsAntioxidantsArchaeaAscorbic AcidAscorbic Acid DeficiencyAutomobile DrivingBacteriaBicarbonatesBindingBiochemicalBiochemical ReactionBiological AssayCarrier ProteinsCellsCessation of lifeCollaborationsCouplingCrohn&aposs diseaseCrystallizationCrystallographyCysteineDNA biosynthesisDependenceDiseaseDrug Binding SiteDrug Delivery SystemsDrug TargetingElectrophysiology (science)ElementsExhibitsFamilyFamily memberFatigueFree Radical ScavengersGene FamilyGoalsHealthHemorrhageHepatitisHomologous GeneHumanImpaired wound healingIndividualInflammatoryIntestinesIonsKidneyKineticsLifeLymphoproliferative DisordersMammalsMeasurementMediatingMembraneMental DepressionMetabolicMethodsMicronutrientsModelingMolecularMolecular ConformationMutationOrganismPathway interactionsPetechiaePharmaceutical PreparationsPharmacotherapyPhysiologyProcessProtein ConformationProteinsProtistaPurinesRNA chemical synthesisRattusRegulationResolutionResourcesRoleScurvySignal TransductionSiteSolid NeoplasmStructureSubstrate SpecificityTherapeuticTimeUrsidae FamilyVirus DiseasesVitaminsabsorptionascorbatecofactorcrosslinkdesignfungusinterestmembermultidisciplinarynucleobasenucleobase analognutritionprotein functionpublic health relevanceradiotracersodium DEPENDENDENT vitamin C transporter 1sodium-dependent vitamin C transporter 2solutestoichiometryuptake
项目摘要
DESCRIPTION (provided by applicant): Members of the nucleobase/ascorbate transporter (NAT) gene family transport nucleobases in all kingdoms of live and vitamin C in mammals. In humans, vitamin C (L-ascorbic acid) is an essential micronutrient that serves as an antioxidant scavenger of free radicals and as a cofactor in many enzymatic reactions. Transport of nucleobases is implicated in crucial processes such as DNA and RNA synthesis, cell signaling, and metabolic regulation. In addition, the cellular delivery of nucleobases has gained special interest in therapeutic applications as nucleobase analogs are currently used in the treatment of solid tumors, lymphoproliferative diseases, viral infections such as hepatitis and AIDS, and some inflammatory diseases, e.g., Crohn's disease. Despite the importance of NATs in health, disease, and pharmacotherapy, detailed information about their transport mechanism, which is crucial to exploit their potential as target for drugs with high efficacy, is limited. In this multple PD/PI proposal we seek to understand mechanistic commonalities and differences among members of the NAT family. Building on our recent exciting identification and crystallization of a bacterial NAT homolog (PaaTCp) at 2.85 Å resolution that transports nucleobases and vitamin C in H+ and Na+-dependent fashion, respectively, this project is designed to elucidate basic mechanisms of substrate recognition and translocation in both bacterial and human NAT family members. We propose the following Specific Aims: (1) to identify the substrate and drug binding site(s). The goal is to co-crystallize PaaTCp with its substrates (purines and vitamin C) and nucleobase analogs and then use the structures as a guide to functionally validate the substrate and drug binding sites by mutational studies in conjunction with radiotracer binding; (2) to develop a model of transport for PaaTCp. The goal is to obtain a quantitative understanding of H+- and Na+-dependent substrate transport, including the identification of the H+ and Na+ sites and the elucidation of the stoichiometry of the potential ion (H+ and Na+) coupling mechanism, and to describe precisely the kinetics of transport; (3) to illustrate conformational changes associated with (co)substrate translocation and how drugs affect these transitions. The goal is to crystallize PaaTCp in outward- and inward-facing conformations, and to use crosslinking and cysteine accessibility assays to validate the structures, or when structures with alternate conformations are not attainable, to deduce conformational changes; (4) to establish the relevance of our structural and functional findings in PaaTCp to understanding the function of the human SVCTs by exploring the key elements of substrate binding, and its coupling to the ion motive force to develop a general applicable mechanistic model of function for proteins with PaaTCp fold.
描述(通过应用证明):哺乳动物中所有王国和维生素C中的核碱/抗坏血酸转运蛋白转运蛋白(NAT)基因家族转运核量。作为自由基的抗氧化剂和许多酶促反应。利息利息利息利息利息利息利息利息利息利息利息利息利息利息利息利息的利息利息利息利息利息,目前使用利息利息利息利息利息。艾滋病和散发性疾病是克罗恩病。 NAT家族的成员之间的差异遵循特定的目的:(1)鉴定底物和药物结合位点及其底物(嘌呤和维生素C)和核碱类似物,并使用结构作为底物和药物结合的指南与Radiotracer结合的研究; H+和Na+)的动力学精确地描述了底物的动力学; 4)通过探索底物结合的关键要素及其与离子动力的耦合,以开发具有PAATCP折叠蛋白的蛋白质功能的一般机械模型,以确定我们在PAATCP中的结构发现的相关性。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Matthias Quick其他文献
Matthias Quick的其他文献
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{{ truncateString('Matthias Quick', 18)}}的其他基金
Structure and mechanism of pendrin and the mutations that cause Pendred's Syndrome
pendrin的结构和机制以及引起Pendred综合征的突变
- 批准号:
10719603 - 财政年份:2023
- 资助金额:
$ 35.32万 - 项目类别:
Molecular mechanism of nucleobase/vitamin C transporters
核碱基/维生素C转运蛋白的分子机制
- 批准号:
9346958 - 财政年份:2016
- 资助金额:
$ 35.32万 - 项目类别:
Molecular mechanism of nucleobase/vitamin C transporters
核碱基/维生素C转运蛋白的分子机制
- 批准号:
9127471 - 财政年份:2016
- 资助金额:
$ 35.32万 - 项目类别:
Molecular mechanism of nucleobase/vitamin C transporters
核碱基/维生素C转运蛋白的分子机制
- 批准号:
9281755 - 财政年份:2016
- 资助金额:
$ 35.32万 - 项目类别:
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