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

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+反转运蛋白1家族底物易位的分子基础

项目成果

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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:
    $ 32.76万
  • 项目类别:
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:
    8262674
  • 财政年份:
    2011
  • 资助金额:
    $ 32.76万
  • 项目类别:

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