Publication Date:
2015-05-15
Description:
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, a substrate analogue 3,4-dichlorophenethylamine, the psychostimulants d-amphetamine and 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469479/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469479/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Kevin H -- Penmatsa, Aravind -- Gouaux, Eric -- F32 MH093120/MH/NIMH NIH HHS/ -- P50 DA018165/DA/NIDA NIH HHS/ -- P50DA018165/DA/NIDA NIH HHS/ -- R37 MH070039/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 May 21;521(7552):322-7. doi: 10.1038/nature14431. Epub 2015 May 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vollum Institute, Oregon Health &Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA. ; 1] Vollum Institute, Oregon Health &Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA [2] Howard Hughes Medical Institute, Oregon Health &Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25970245" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antidepressive Agents/chemistry/metabolism
;
Binding Sites
;
Central Nervous System Stimulants/chemistry/*metabolism
;
Chlorides/metabolism
;
Cocaine/analogs & derivatives/chemistry/metabolism
;
Crystallography, X-Ray
;
Dextroamphetamine/chemistry/metabolism
;
Dopamine/analogs & derivatives/chemistry/metabolism
;
Dopamine Plasma Membrane Transport Proteins/*chemistry/*metabolism
;
Drosophila melanogaster/*chemistry
;
Ligands
;
Methamphetamine/chemistry/metabolism
;
Models, Molecular
;
Molecular Conformation
;
Neurotransmitter Agents/chemistry/*metabolism
;
Phenethylamines/metabolism
;
Protein Stability
;
Sodium/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink