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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：
Min Lu
金额：
$ 32.76万
依托单位：
ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
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：
https://reporter.nih.gov/project-details/10414517
关键词：
Alcoholism Amino Acids Antimicrobial Resistance Binding Biochemical Biological Bipolar Disorder Brain Cations Cell membrane Cells Chemical Structure Clinical Communicable Diseases Complex Coupled Couples Data Development Drug Binding Site Drug Efflux Drug Modelings Escherichia coli Family Gilles de la Tourette syndrome Goals Human Huntington Disease Infection Integral Membrane Protein Lead Ligands Light Major Depressive Disorder Malignant Neoplasms Mediating Membrane Membrane Proteins Mental Depression Modeling Molecular Movement Multi-Drug Resistance Mutagenesis Mutate Neuromodulator Neurotoxins Neurotransmitters Parkinson Disease Pathogenicity Patients Pharmaceutical Preparations Physiological Polyamines Process Protein Export Pathway Proteins Publishing Reporting Research Roentgen Rays Schizophrenia Site Structure Therapeutic Transmembrane Transport Treatment Efficacy Variant Work alcoholism therapy antimicrobial antiport antiporter autism spectrum disorder base clinically relevant deprotonation effective therapy experience inhibitor insight membrane model microorganism monoamine multi drug transporter mutant nervous system disorder neuropsychiatry neurotransmission novel strategies novel therapeutic intervention overexpression pathogenic bacteria protonation solute structural biology targeted treatment therapeutic target unpublished works vesicle transport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+反转运蛋白1家族底物易位的分子基础