PDBsum entry 4xph

Protein transport/inhibitor

PDB id: 4xph

Contents

Protein chains

534 a.a.

214 a.a.

219 a.a.

Ligands

BGC-GLC

P4G

42J

CLR ×2

Metals

_NA ×3

_CL

Waters ×15

References listed in PDB file

Key reference

• Title: Neurotransmitter and psychostimulant recognition by the dopamine transporter.
• Authors: K.H.Wang, A.Penmatsa, E.Gouaux.
• Ref.: Nature, 2015, 521, 322-327. [DOI no: 10.1038/nature14431]
• PubMed id: 25970245

Abstract

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.