Molecular Basis of Substrate Translocation in the Drug/H+ Antiporter 1 Family
药物/H 逆向转运蛋白 1 家族底物易位的分子基础
基本信息
- 批准号:10414517
- 负责人:
- 金额:$ 32.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-15 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AlcoholismAmino AcidsAntimicrobial ResistanceBindingBiochemicalBiologicalBipolar DisorderBrainCationsCell membraneCellsChemical StructureClinicalCommunicable DiseasesComplexCoupledCouplesDataDevelopmentDrug Binding SiteDrug EffluxDrug ModelingsEscherichia coliFamilyGilles de la Tourette syndromeGoalsHumanHuntington DiseaseInfectionIntegral Membrane ProteinLeadLigandsLightMajor Depressive DisorderMalignant NeoplasmsMediatingMembraneMembrane ProteinsMental DepressionModelingMolecularMovementMulti-Drug ResistanceMutagenesisMutateNeuromodulatorNeurotoxinsNeurotransmittersParkinson DiseasePathogenicityPatientsPharmaceutical PreparationsPhysiologicalPolyaminesProcessProtein Export PathwayProteinsPublishingReportingResearchRoentgen RaysSchizophreniaSiteStructureTherapeuticTransmembrane TransportTreatment EfficacyVariantWorkalcoholism therapyantimicrobialantiportantiporterautism spectrum disorderbaseclinically relevantdeprotonationeffective therapyexperienceinhibitorinsightmembrane modelmicroorganismmonoaminemulti drug transportermutantnervous system disorderneuropsychiatryneurotransmissionnovel strategiesnovel therapeutic interventionoverexpressionpathogenic bacteriaprotonationsolutestructural biologytargeted treatmenttherapeutic targetunpublished worksvesicle transport
项目摘要
Molecular Basis of Substrate Translocation in the Drug/H+ Antiporter 1 Family
Summary
Integral membrane proteins known as multidrug transporters extrude therapeutic drugs of diverse
chemical structures across cell membranes, impeding the treatment of human cancers, infectious
diseases, and neurological disorders. Currently we lack a deep and mechanistic understanding of how
these proteins export drugs or how they can be thwarted. We will study the structure and mechanism
of a model multidrug transporter, MdfA from Escherichia coli, which couples the influx of H+ to the
efflux of various antimicrobials and belongs to the ubiquitous Drug/H+ Antiporter 1 (DHA1) family.
MdfA orthologues are present in many pathogenic microorganisms, and the overexpression of E. coli
MdfA can lead to antimicrobial resistance in clinical patients. Thus, MdfA represents an important
target for therapeutic exploitation to overcome multidrug resistance. Furthermore, the SLC18
antiporters, which are the human counterparts of MdfA in the DHA1 family, conduct the H+-dependent
vesicular transport of monoamine neurotransmitters, polyamine neuromodulators, and neurotoxins.
The human SLC18 antiporters are essential for brain function and promising therapeutic targets for
battling alcoholism, autism spectrum disorders, bipolar disorder, Huntington disease, major depressive
disorder, Parkinson’s disease, schizophrenia, and Tourette syndrome. Our long-term objective is to
understand how the DHA1 multidrug transporters and human SLC18 antiporters translocate their
substrates and how their function can be modulated for potential therapeutic benefit. Notably, prior
biochemical studies have suggested that MdfA translocates certain substrates via a non-canonical
mechanism. Drawing upon these data and our experience in membrane protein structural biology, we
will accomplish two aims: (1) to elucidate the molecular basis for simultaneous translocation of two
mono-cationic substrates by a DHA1; (2) to reveal the structural mechanism for non-canonical, DHA1-
mediated extrusion of di-cationic therapeutics. By combining crystallographic and biochemical studies,
we will acquire new insights into how a DHA1 translocates two substrates concurrently, how a DHA1
inhibitor differs from the substrate, and how a DHA1 exports a therapeutic drug in two consecutive and
yet different deprotonation/protonation cycles. The new conceptual framework and DHA1 structures
obtained from this study will serve as a stepping-stone toward devising novel strategies to evade or
inhibit the clinically relevant multidrug transporters, which may rescue therapeutic efficacy against
multidrug-resistant cells and halt the spread of untreatable infections. Furthermore, our work will offer
a springboard for the mechanistic studies of human SLC18 antiporters, which will shed new light on
how they utilize the electrochemical H+ gradient to translocate monoamine neurotransmitters,
neurotoxins, or polyamine neuromodulators, across vesicular membranes.
药物/H+逆向转运蛋白1家族底物转位的分子基础
摘要
被称为多药物转运体的整膜蛋白挤出不同种类的治疗药物
穿过细胞膜的化学结构,阻碍人类癌症的治疗,传染性
疾病和神经紊乱。目前,我们缺乏深入和机械性的理解
这些蛋白质输出药物或它们如何被挫败。我们将研究其结构和机制。
一种多药物转运体的模型,来自大肠杆菌的MDFA,它将H+的内流耦合到
是多种抗菌药的外排产物,属于无处不在的药物/H+逆向转运蛋白1(DHA1)家族。
MDFA同源异构体存在于许多致病微生物中,而大肠杆菌的过度表达
MDFA可导致临床患者产生耐药性。因此,千年发展目标代表着一个重要的
治疗利用的目标,以克服多药耐药。此外,SLC18
反转运蛋白是DHA1家族中MDFA的人类对应物,它进行H+依赖的
单胺类神经递质、多胺类神经调节剂和神经毒素的囊泡运输。
人类SLC18逆向转运蛋白对大脑功能是必不可少的,并有望成为治疗癌症的靶点
与酒精中毒、自闭症谱系障碍、双相情感障碍、亨廷顿病、重度抑郁症作斗争
精神障碍、帕金森氏症、精神分裂症和多发性抽动症。我们的长期目标是
了解DHA1多药转运体和人类SLC18反转运体是如何将其
底物以及如何调节它们的功能以获得潜在的治疗益处。值得注意的是,之前
生化研究表明,MDFA通过非规范的
机制。根据这些数据和我们在膜蛋白结构生物学方面的经验,我们
将实现两个目标:(1)阐明两个基因同时易位的分子基础
(2)揭示非正则DHA1-的结构机理。
双阳离子治疗剂的介导性挤出。通过结合结晶学和生物化学研究,
我们将对DHA1如何同时转移两种底物、DHA1如何
抑制剂与底物不同,以及DHA1如何在连续的两个和
然而,不同的去质子化/质子化周期。新的概念框架和DHA1结构
从这项研究中获得的将作为设计新策略的垫脚石,以逃避或
抑制临床相关的多药转运蛋白,可能挽救治疗效果
多药耐药细胞和阻止无法治愈的感染的传播。此外,我们的工作将提供
为人类SLC18逆向转运蛋白的机制研究提供了一个跳板,这将为
他们如何利用电化学H+梯度来转移单胺类神经递质,
神经毒素,或多胺神经调节剂,穿过囊泡膜。
项目成果
期刊论文数量(0)
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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Min Lu其他文献
Min Lu的其他文献
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{{ truncateString('Min Lu', 18)}}的其他基金
Molecular Basis of Substrate Translocation in the Drug/H+ Antiporter 1 Family
药物/H 逆向转运蛋白 1 家族底物易位的分子基础
- 批准号:
10644018 - 财政年份:2022
- 资助金额:
$ 32.76万 - 项目类别:
Development of novel small-molecule inhibitors of HIV-1 fusion as microbicides
作为杀微生物剂的新型 HIV-1 融合小分子抑制剂的开发
- 批准号:
8892301 - 财政年份:2014
- 资助金额:
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Engineered Envelope Glycoprotein Trimers for HIV-1 Vaccine Immunogens
用于 HIV-1 疫苗免疫原的工程包膜糖蛋白三聚体
- 批准号:
8743611 - 财政年份:2014
- 资助金额:
$ 32.76万 - 项目类别:
Small-molecule inhibitors of gp41-mediated fusion as HIV-1 topical microbicides
gp41 介导融合的小分子抑制剂作为 HIV-1 局部杀菌剂
- 批准号:
8743614 - 财政年份:2014
- 资助金额:
$ 32.76万 - 项目类别:
The Role of Scavenger Receptor gp340 in Mucosal HIV-1 Transmission and Inhibition
清道夫受体 gp340 在粘膜 HIV-1 传播和抑制中的作用
- 批准号:
8743609 - 财政年份:2014
- 资助金额:
$ 32.76万 - 项目类别:
The Role of Scavenger Receptor gp340 in Mucosal HIV-1 Transmission and Inhibition
清道夫受体 gp340 在粘膜 HIV-1 传播和抑制中的作用
- 批准号:
8607113 - 财政年份:2011
- 资助金额:
$ 32.76万 - 项目类别:
The Role of Scavenger Receptor gp340 in Mucosal HIV-1 Transmission and Inhibition
清道夫受体 gp340 在粘膜 HIV-1 传播和抑制中的作用
- 批准号:
8230476 - 财政年份:2011
- 资助金额:
$ 32.76万 - 项目类别:
Development of an HIV-1 entry inhibitor pre-drug as a microbicide
开发作为杀微生物剂的 HIV-1 进入抑制剂前药
- 批准号:
8112130 - 财政年份:2011
- 资助金额:
$ 32.76万 - 项目类别:
The Role of Scavenger Receptor gp340 in Mucosal HIV-1 Transmission and Inhibition
清道夫受体 gp340 在粘膜 HIV-1 传播和抑制中的作用
- 批准号:
8704604 - 财政年份:2011
- 资助金额:
$ 32.76万 - 项目类别:
Development of an HIV-1 entry inhibitor pre-drug as a microbicide
开发作为杀微生物剂的 HIV-1 进入抑制剂前药
- 批准号:
8714598 - 财政年份:2011
- 资助金额:
$ 32.76万 - 项目类别:
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