Computational and Biochemical Docking of the Irreversible Cocaine Analog RTI 82 Directly Demonstrates Ligand Positioning in the Dopamine Transporter Central Substrate-binding Site

Dahal, Rejwi; Pramod, Akula Bala; Sharma, Babita; Krout, Danielle; Foster, James D.; Hwan, Joo; Cao, Jianjing; Newman, Amy Hauck; Lever, John R.; Vaughan, Roxanne A.; Henry, L. Keith

doi:10.1074/jbc.m114.571521

Cited by 25 publications

(40 citation statements)

References 103 publications

(82 reference statements)

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“…The side chain of Phe 319 maintains a similar orientation as seen in the dDAT-nortriptyline structure due to the bulky tropane ring and the methyl ester group present in all three tropane inhibitors. Overall, the docking and photolabeling studies predicted the location and orientation of cocaine and its analogues to overlap with the DA-binding site of DAT 25,26,30 . Our structures validate these findings yet indicate distinctions that have implications for the mechanism of inhibition by tropane ligands.…”

Section: Cocaine Binds In the Central Sitementioning

confidence: 95%

“…Ligand docking studies using a homology model of DAT, in combination with biochemical binding assays and ligand-dependent disulfide trapping experiments, have probed the orientation of cocaine in the central binding site 25,26,30 . These studies predicted that the fluorophenyl moiety of β–CFT forms a hydrogen bond with the side chain equivalent to Asn 125 in dDAT.…”

Section: Cocaine Binds In the Central Sitementioning

confidence: 99%

“…Mutagenesis, chemical modification, binding and transport studies have implicated the central or S1 binding site in DAT, akin to the leucine and tryptophan site in LeuT, as the binding site occupied by DA, amphetamines, cocaine and antidepressants 25,26,30 . Moreover, the x-ray structure of a transport-inactive Drosophila melanogaster DAT (dDAT) in complex with nortriptyline shows the antidepressant bound at the central site 9,31 .…”

Section: Introductionmentioning

confidence: 99%

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Neurotransmitter and psychostimulant recognition by the dopamine transporter

Wang

Penmatsa

Gouaux

2015

Nature

390

548

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Na+/Cl−-coupled biogenic amine transporters are the primary targets of therapeutic and abused drugs, ranging from antidepressants to the psychostimulants cocaine and amphetamines, and to their cognate substrates. Here we determine x-ray crystal structures of the Drosophila melanogaster dopamine transporter (dDAT) bound to its substrate dopamine (DA), a substrate analogue 3,4-dichlorophenethylamine, the psychostimulants D-amphetamine, methamphetamine, or to cocaine and cocaine analogues. All ligands bind to the central binding site, located approximately halfway across the membrane bilayer, in close proximity to bound sodium and chloride ions. The central binding site recognizes three chemically distinct classes of ligands via conformational changes that accommodate varying sizes and shapes, thus illustrating molecular principles that distinguish substrates from inhibitors in biogenic amine transporters.

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Section: Cocaine Binds In the Central Sitementioning

confidence: 95%

Section: Cocaine Binds In the Central Sitementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Neurotransmitter and psychostimulant recognition by the dopamine transporter

Wang

Penmatsa

Gouaux

2015

Nature

390

548

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“…Allosteric ligands of the DAT have been detected by pharmacological methods (Rothman et al, 2009). Photoaffinity labeling of the DAT by a cocaine analog and molecular modeling have established its binding site location (Dahal et al, 2014). The combination of binding enhancement and functional inhibition by the nucleoside derivatives suggests possible allosteric binding with respect to the tropanes.…”

Section: Discussionmentioning

confidence: 99%

Rigid Adenine Nucleoside Derivatives as Novel Modulators of the Human Sodium Symporters for Dopamine and Norepinephrine

Janowsky

Tosh

Eshleman

2016

Journal of Pharmacology and Experimental Therapeutics

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Thirty-two congeneric rigid adenine nucleoside derivatives containing a North (N)-methanocarba ribose substitution and a 2-arylethynyl group either enhanced (up to 760% of control) or inhibited [ potent DA uptake inhibitor (compound 6) with an IC 50 value of 92 nM (3-fold more potent than cocaine), but not nitrogen heterocycles. Several compounds inhibited or enhanced binding at the norepinephrine transporter (NET) and serotonin transporter (SERT) and inhibited function in the micromolar range; truncation at the 49-position in compound 23 allowed for weak inhibition of the SERT. We have not yet eliminated adenosine receptor affinity from this class of DAT modulators, but we identified modifications that remove DAT inhibition as an off-target effect of potent adenosine receptor agonists. Thus, we have identified a new class of allosteric DAT ligands, rigidified adenosine derivatives, and explored their initial structural requirements. They display a very atypical pharmacological profile, i.e., either enhancement by increasing affinity or inhibition of radioligand binding at the DAT, and in some cases the NET and SERT, and inhibition of neurotransmitter uptake.

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“…1). DAT structural and transport mechanism details have been elucidated by homology to the crystallized bacterial leucine transporter (LeuT) and the Drosophila (d)DAT, which facilitated the identification of the helix packing arrangement, substrate active site and translocation pathway, and extracellular and intracellular gating networks that dictate substrate movement (Beuming et al , 2006; Dahal et al , 2014; Wang et al , 2015). The inner core that forms the permeation pathway consists primarily of TMD1, TMD3, TMD6, and TMD8 (Fig.…”

Section: Transport Mechanismmentioning

confidence: 99%

Palmitoylation mechanisms in dopamine transporter regulation

Rastedt

Vaughan

Foster

2017

Journal of Chemical Neuroanatomy

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The neurotransmitter dopamine (DA) plays a key role in several biological processes including reward, mood, motor activity and attention. Synaptic DA homeostasis is controlled by the dopamine transporter (DAT) which transports extracellular DA into the presynaptic neuron after release and regulates its availability to receptors. Many neurological disorders such as schizophrenia, bipolar disorder, Parkinson disease and attention-deficit hyperactivity disorder are associated with imbalances in DA homeostasis that may be related to DAT dysfunction. DAT is also a target of psychostimulant and therapeutic drugs that inhibit DA reuptake and lead to elevated dopaminergic neurotransmission. We have recently demonstrated the acute and chronic modulation of DA reuptake activity and DAT stability through S-palmitoylation, the linkage of a 16-carbon palmitate group to cysteine via a thioester bond. This review summarizes the properties and regulation of DAT palmitoylation and describes how it serves to affect various transporter functions. Better understanding of the role of palmitoylation in regulation of DAT function may lead to identification of therapeutic targets for modulation of DA homeostasis in the treatment of dopaminergic disorders.

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Computational and Biochemical Docking of the Irreversible Cocaine Analog RTI 82 Directly Demonstrates Ligand Positioning in the Dopamine Transporter Central Substrate-binding Site

Cited by 25 publications

References 103 publications

Neurotransmitter and psychostimulant recognition by the dopamine transporter

Neurotransmitter and psychostimulant recognition by the dopamine transporter

Rigid Adenine Nucleoside Derivatives as Novel Modulators of the Human Sodium Symporters for Dopamine and Norepinephrine

Palmitoylation mechanisms in dopamine transporter regulation

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