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Article: Structural mechanisms for VMAT2 inhibition by tetrabenazine.

Dalton, Michael P / Cheng, Mary Hongying / Bahar, Ivet / Coleman, Jonathan A

bioRxiv : the preprint server for biology

2024

Abstract: The vesicular monoamine transporter 2 (VMAT2) is a proton-dependent antiporter responsible for loading monoamine neurotransmitters into synaptic vesicles. Dysregulation of VMAT2 can lead to several neuropsychiatric disorders including Parkinson's disease ...

Abstract	The vesicular monoamine transporter 2 (VMAT2) is a proton-dependent antiporter responsible for loading monoamine neurotransmitters into synaptic vesicles. Dysregulation of VMAT2 can lead to several neuropsychiatric disorders including Parkinson's disease and schizophrenia. Furthermore, drugs such as amphetamine and MDMA are known to act on VMAT2, exemplifying its role in the mechanisms of actions for drugs of abuse. Despite VMAT2's importance, there remains a critical lack of mechanistic understanding, largely driven by a lack of structural information. Here we report a 3.1 Å resolution cryo-EM structure of VMAT2 complexed with tetrabenazine (TBZ), a non-competitive inhibitor used in the treatment of Huntington's chorea. We find TBZ interacts with residues in a central binding site, locking VMAT2 in an occluded conformation and providing a mechanistic basis for non-competitive inhibition. We further identify residues critical for cytosolic and lumenal gating, including a cluster of hydrophobic residues which are involved in a lumenal gating strategy. Our structure also highlights three distinct polar networks that may determine VMAT2 conformational dynamics and play a role in proton transduction. The structure elucidates mechanisms of VMAT2 inhibition and transport, providing insights into VMAT2 architecture, function, and the design of small-molecule therapeutics.
Language	English
Publishing date	2024-02-01
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.05.556211
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Article ; Online: Structural mechanisms for VMAT2 inhibition by tetrabenazine.

Dalton, Michael P / Cheng, Mary Hongying / Bahar, Ivet / Coleman, Jonathan A

eLife

2024 Volume 12

Abstract	The vesicular monoamine transporter 2 (VMAT2) is a proton-dependent antiporter responsible for loading monoamine neurotransmitters into synaptic vesicles. Dysregulation of VMAT2 can lead to several neuropsychiatric disorders including Parkinson's disease and schizophrenia. Furthermore, drugs such as amphetamine and MDMA are known to act on VMAT2, exemplifying its role in the mechanisms of actions for drugs of abuse. Despite VMAT2's importance, there remains a critical lack of mechanistic understanding, largely driven by a lack of structural information. Here, we report a 3.1 Å resolution cryo-electron microscopy (cryo-EM) structure of VMAT2 complexed with tetrabenazine (TBZ), a non-competitive inhibitor used in the treatment of Huntington's chorea. We find TBZ interacts with residues in a central binding site, locking VMAT2 in an occluded conformation and providing a mechanistic basis for non-competitive inhibition. We further identify residues critical for cytosolic and lumenal gating, including a cluster of hydrophobic residues which are involved in a lumenal gating strategy. Our structure also highlights three distinct polar networks that may determine VMAT2 conformational dynamics and play a role in proton transduction. The structure elucidates mechanisms of VMAT2 inhibition and transport, providing insights into VMAT2 architecture, function, and the design of small-molecule therapeutics.
MeSH term(s)	Humans ; Tetrabenazine/metabolism ; Tetrabenazine/pharmacology ; Vesicular Monoamine Transport Proteins/chemistry ; Vesicular Monoamine Transport Proteins/metabolism ; Protons ; Cryoelectron Microscopy ; Huntington Disease
Chemical Substances	Tetrabenazine (Z9O08YRN8O) ; Vesicular Monoamine Transport Proteins ; Protons
Language	English
Publishing date	2024-03-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.91973
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Monoamine transporters: structure, intrinsic dynamics and allosteric regulation.

Cheng, Mary Hongying / Bahar, Ivet

Nature structural & molecular biology

2019 Volume 26, Issue 7, Page(s) 545–556

Abstract: Monoamine transporters (MATs) regulate neurotransmission via the reuptake of dopamine, serotonin and norepinephrine from extra-neuronal regions and thus maintain neurotransmitter homeostasis. As targets of a wide range of compounds, including ... ...

Abstract	Monoamine transporters (MATs) regulate neurotransmission via the reuptake of dopamine, serotonin and norepinephrine from extra-neuronal regions and thus maintain neurotransmitter homeostasis. As targets of a wide range of compounds, including antidepressants, substances of abuse and drugs for neuropsychiatric and neurodegenerative disorders, their mechanism of action and their modulation by small molecules have long been of broad interest. Recent advances in the structural characterization of dopamine and serotonin transporters have opened the way for structure-based modeling and simulations, which, together with experimental data, now provide mechanistic understanding of their transport function and interactions. Here we review recent progress in the elucidation of the structural dynamics of MATs and their conformational landscape and transitions, as well as allosteric regulation mechanisms.
MeSH term(s)	Allosteric Regulation/drug effects ; Animals ; Binding Sites/drug effects ; Dopamine Plasma Membrane Transport Proteins/chemistry ; Dopamine Plasma Membrane Transport Proteins/metabolism ; Drug Discovery ; Humans ; Models, Molecular ; Norepinephrine Plasma Membrane Transport Proteins/chemistry ; Norepinephrine Plasma Membrane Transport Proteins/metabolism ; Protein Conformation/drug effects ; Serotonin Plasma Membrane Transport Proteins/chemistry ; Serotonin Plasma Membrane Transport Proteins/metabolism
Chemical Substances	Dopamine Plasma Membrane Transport Proteins ; Norepinephrine Plasma Membrane Transport Proteins ; Serotonin Plasma Membrane Transport Proteins
Language	English
Publishing date	2019-07-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2126708-X
ISSN	1545-9985 ; 1545-9993
ISSN (online)	1545-9985
ISSN	1545-9993
DOI	10.1038/s41594-019-0253-7
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Article ; Online: Synthesis and Structure-Activity Relationships for Glutamate Transporter Allosteric Modulators.

Fontana, Andréia C K / Poli, Adi N R / Gour, Jitendra / Srikanth, Yellamelli V V / Anastasi, Nicholas / Ashok, Devipriya / Khatiwada, Apeksha / Reeb, Katelyn L / Cheng, Mary Hongying / Bahar, Ivet / Rawls, Scott M / Salvino, Joseph M

Journal of medicinal chemistry

2024 Volume 67, Issue 8, Page(s) 6119–6143

Abstract: Excitatory amino acid transporters (EAATs) are essential CNS proteins that regulate glutamate levels. Excess glutamate release and alteration in EAAT expression are associated with several CNS disorders. Previously, we identified positive allosteric ... ...

Abstract	Excitatory amino acid transporters (EAATs) are essential CNS proteins that regulate glutamate levels. Excess glutamate release and alteration in EAAT expression are associated with several CNS disorders. Previously, we identified positive allosteric modulators (PAM) of EAAT2, the main CNS transporter, and have demonstrated their neuroprotective properties
MeSH term(s)	Structure-Activity Relationship ; Allosteric Regulation/drug effects ; Humans ; Excitatory Amino Acid Transporter 2/metabolism ; HEK293 Cells ; Animals ; Molecular Structure
Chemical Substances	Excitatory Amino Acid Transporter 2
Language	English
Publishing date	2024-04-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.3c01909
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Article ; Online: Structural basis of G protein–Coupled receptor CMKLR1 activation and signaling induced by a chemerin-derived agonist

Xuan Zhang / Tina Weiß / Mary Hongying Cheng / Siqi Chen / Carla Katharina Ambrosius / Anne Sophie Czerniak / Kunpeng Li / Mingye Feng / Ivet Bahar / Annette G. Beck-Sickinger / Cheng Zhang

PLoS Biology, Vol 21, Iss

2023 Volume 12

Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Multisystem Inflammatory Syndrome in Children and Long COVID: The SARS-CoV-2 Viral Superantigen Hypothesis.

Noval Rivas, Magali / Porritt, Rebecca A / Cheng, Mary Hongying / Bahar, Ivet / Arditi, Moshe

Frontiers in immunology

2022 Volume 13, Page(s) 941009

Abstract: Multisystem inflammatory syndrome in children (MIS-C) is a febrile pediatric inflammatory disease that may develop weeks after initial SARS-CoV-2 infection or exposure. MIS-C involves systemic hyperinflammation and multiorgan involvement, including ... ...

Abstract	Multisystem inflammatory syndrome in children (MIS-C) is a febrile pediatric inflammatory disease that may develop weeks after initial SARS-CoV-2 infection or exposure. MIS-C involves systemic hyperinflammation and multiorgan involvement, including severe cardiovascular, gastrointestinal (GI) and neurological symptoms. Some clinical attributes of MIS-C-such as persistent fever, rashes, conjunctivitis and oral mucosa changes (red fissured lips and strawberry tongue)-overlap with features of Kawasaki disease (KD). In addition, MIS-C shares striking clinical similarities with toxic shock syndrome (TSS), which is triggered by bacterial superantigens (SAgs). The remarkable similarities between MIS-C and TSS prompted a search for SAg-like structures in the SARS-CoV-2 virus and the discovery of a unique SAg-like motif highly similar to a Staphylococcal enterotoxin B (SEB) fragment in the SARS-CoV-2 spike 1 (S1) glycoprotein. Computational studies suggest that the SAg-like motif has a high affinity for binding T-cell receptors (TCRs) and MHC Class II proteins. Immunosequencing of peripheral blood samples from MIS-C patients revealed a profound expansion of TCR β variable gene 11-2 (TRBV11-2), which correlates with MIS-C severity and serum cytokine levels, consistent with a SAg-triggered immune response. Computational sequence analysis of SARS-CoV-2 spike further identified conserved neurotoxin-like motifs which may alter neuronal cell function and contribute to neurological symptoms in COVID-19 and MIS-C patients. Additionally, autoantibodies are detected during MIS-C, which may indicate development of post-SARS-CoV-2 autoreactive and autoimmune responses. Finally, prolonged persistence of SARS-CoV-2 RNA in the gut, increased gut permeability and elevated levels of circulating S1 have been observed in children with MIS-C. Accordingly, we hypothesize that continuous and prolonged exposure to the viral SAg-like and neurotoxin-like motifs in SARS-CoV-2 spike may promote autoimmunity leading to the development of post-acute COVID-19 syndromes, including MIS-C and long COVID, as well as the neurological complications resulting from SARS-CoV-2 infection.
MeSH term(s)	COVID-19/complications ; Child ; Connective Tissue Diseases ; Humans ; Neurotoxins ; RNA, Viral ; SARS-CoV-2 ; Superantigens ; Systemic Inflammatory Response Syndrome ; Post-Acute COVID-19 Syndrome
Chemical Substances	Neurotoxins ; RNA, Viral ; Superantigens
Language	English
Publishing date	2022-07-07
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.941009
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Article ; Online: The Alkylamine Stimulant 1,3-Dimethylamylamine Exhibits Substrate-Like Regulation of Dopamine Transporter Function and Localization.

Small, Cassandra / Cheng, Mary Hongying / Belay, Saron S / Bulloch, Sarah L / Zimmerman, Brooke / Sorkin, Alexander / Block, Ethan R

The Journal of pharmacology and experimental therapeutics

2023 Volume 386, Issue 2, Page(s) 266–273

Abstract: The alkylamine stimulant 1,3-dimethylamylamine (DMAA) is used nonmedically as an appetite suppressant and exercise performance enhancer despite adverse cardiovascular effects that have limited its legal status. There is scant research describing the ... ...

Abstract	The alkylamine stimulant 1,3-dimethylamylamine (DMAA) is used nonmedically as an appetite suppressant and exercise performance enhancer despite adverse cardiovascular effects that have limited its legal status. There is scant research describing the mechanism of action of DMAA, making it difficult to gauge risks or therapeutic potential. An important molecular target of structurally related phenethylamines, such as amphetamine, for regulating mood, cognition, movement, and the development of substance use disorder is the dopamine transporter, which limits the range and magnitude of dopamine signaling via reuptake from the extracellular space. The present studies were therefore initiated to characterize the effects of DMAA on dopamine transporter function. Specifically, we tested the hypothesis that DMAA exhibits substrate-like effects on dopamine transporter function and trafficking. In transport assays in human embryonic kidney cells, DMAA inhibited dopamine uptake by the human dopamine transporter in a competitive manner. Docking analysis and molecular dynamics simulations supported these findings, revealing that DMAA binds to the S1 substrate binding site and induces a conformational change from outward-facing open to outward-facing closed states, similar to the known substrates. Further supporting substrate-like effects of DMAA, the drug stimulated dopamine transporter endocytosis in a heterologous expression system via cocaine- and protein kinase A-sensitive mechanisms, mirroring findings with amphetamine. Together, these data indicate that DMAA elicits neurologic effects by binding to and regulating function of the dopamine transporter. Furthermore, pharmacologic distinctions from amphetamine reveal structural determinants for regulating transporter conformation and add mechanistic insight for the regulation of dopamine transporter endocytosis. SIGNIFICANCE STATEMENT: The alkylamine stimulant 1,3-dimethylamylamine (DMAA) is used as an appetite suppressant and athletic performance enhancer and is structurally similar to amphetamine, but there is scant research describing its mechanism of action. Characterizing the effects of DMAA on dopamine transporter function supports evaluation of potential risks and therapeutic potential while also revealing mechanistic details of dynamic transporter-substrate interactions.
MeSH term(s)	Humans ; Dopamine Plasma Membrane Transport Proteins/metabolism ; Appetite Depressants ; Dopamine/metabolism ; Cocaine/pharmacology ; Amphetamine/pharmacology ; Central Nervous System Agents
Chemical Substances	1,3-dimethylamylamine ; Dopamine Plasma Membrane Transport Proteins ; Appetite Depressants ; Dopamine (VTD58H1Z2X) ; Cocaine (I5Y540LHVR) ; Amphetamine (CK833KGX7E) ; Central Nervous System Agents
Language	English
Publishing date	2023-06-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.122.001573
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Article ; Online: Impact of new variants on SARS-CoV-2 infectivity and neutralization: A molecular assessment of the alterations in the spike-host protein interactions.

Cheng, Mary Hongying / Krieger, James M / Banerjee, Anupam / Xiang, Yufei / Kaynak, Burak / Shi, Yi / Arditi, Moshe / Bahar, Ivet

iScience

2022 Volume 25, Issue 3, Page(s) 103939

Abstract: The emergence of SARS-CoV-2 variants necessitates rational assessment of their impact on the recognition and neutralization of the virus by the host cell. We present a comparative analysis of the interactions of Alpha, Beta, Gamma, and Delta variants ... ...

Abstract	The emergence of SARS-CoV-2 variants necessitates rational assessment of their impact on the recognition and neutralization of the virus by the host cell. We present a comparative analysis of the interactions of Alpha, Beta, Gamma, and Delta variants with cognate molecules (ACE2 and/or furin), neutralizing nanobodies (Nbs), and monoclonal antibodies (mAbs) using
Language	English
Publishing date	2022-02-17
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2022.103939
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Article: Structural basis of CMKLR1 signaling induced by chemerin9.

Zhang, Xuan / Weiß, Tina / Cheng, Mary Hongying / Chen, Siqi / Ambrosius, Carla Katharina / Czerniak, Anne Sophie / Li, Kunpeng / Feng, Mingye / Bahar, Ivet / Beck-Sickinger, Annette G / Zhang, Cheng

bioRxiv : the preprint server for biology

2023

Abstract: Chemokine-like receptor 1 (CMKLR1), also known as chemerin receptor 23 (ChemR23) or chemerin receptor 1, is a chemoattractant G protein-coupled receptor (GPCR) that responds to the adipokine chemerin and is highly expressed in innate immune cells, ... ...

Abstract	Chemokine-like receptor 1 (CMKLR1), also known as chemerin receptor 23 (ChemR23) or chemerin receptor 1, is a chemoattractant G protein-coupled receptor (GPCR) that responds to the adipokine chemerin and is highly expressed in innate immune cells, including macrophages and neutrophils. The signaling pathways of CMKLR1 can lead to both pro- and anti-inflammatory effects depending on the ligands and physiological contexts. To understand the molecular mechanisms of CMKLR1 signaling, we determined a high-resolution cryo-electron microscopy (cryo-EM) structure of the CMKLR1-G
Language	English
Publishing date	2023-06-10
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.06.09.544295
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Article ; Online: Functional Characterization of the Dopaminergic Psychostimulant Sydnocarb as an Allosteric Modulator of the Human Dopamine Transporter

Shaili Aggarwal / Mary Hongying Cheng / Joseph M. Salvino / Ivet Bahar / Ole Valente Mortensen

Biomedicines, Vol 9, Iss 634, p

2021 Volume 634

Abstract: The dopamine transporter (DAT) serves a critical role in controlling dopamine (DA)-mediated neurotransmission by regulating the clearance of DA from the synapse and extrasynaptic regions and thereby modulating DA action at postsynaptic DA receptors. ... ...

Abstract	The dopamine transporter (DAT) serves a critical role in controlling dopamine (DA)-mediated neurotransmission by regulating the clearance of DA from the synapse and extrasynaptic regions and thereby modulating DA action at postsynaptic DA receptors. Major drugs of abuse such as amphetamine and cocaine interact with DATs to alter their actions resulting in an enhancement in extracellular DA concentrations. We previously identified a novel allosteric site in the DAT and the related human serotonin transporter that lies outside the central orthosteric substrate- and cocaine-binding pocket. Here, we demonstrate that the dopaminergic psychostimulant sydnocarb is a ligand of this novel allosteric site. We identified the molecular determinants of the interaction between sydnocarb and DAT at the allosteric site using molecular dynamics simulations. Biochemical-substituted cysteine scanning accessibility experiments have supported the computational predictions by demonstrating the occurrence of specific interactions between sydnocarb and amino acids within the allosteric site. Functional dopamine uptake studies have further shown that sydnocarb is a noncompetitive inhibitor of DAT in accord with the involvement of a site different from the orthosteric site in binding this psychostimulant. Finally, DA uptake studies also demonstrate that sydnocarb affects the interaction of DAT with both cocaine and amphetamine. In summary, these studies further strengthen the prospect that allosteric modulation of DAT activity could have therapeutic potential.
Keywords	dopamine transporter ; allosteric modulation ; transport activity ; Biology (General) ; QH301-705.5
Subject code	500
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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