2014
DOI: 10.1074/jbc.m114.571521
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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

Abstract: Background: Cocaine interaction with DAT was assessed using the irreversible binding cocaine analog RTI 82. Results: Molecular modeling and peptide mapping identify adduction of RTI 82 to Phe-319 and Phe-320 of rat DAT and human DAT, respectively. Conclusion: Tropane-based pharmacophores bind to DAT in the central substrate site. Significance: Mapping the cocaine-binding site reveals new insights for medication discovery.

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Cited by 25 publications
(40 citation 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%
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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%
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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%
“…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%