the substrate-driven transition to an inward-facing conformation in the functional mechanism of the dopamine transportersubstrate-driven过渡到一个内部构造的多巴胺转运蛋白的功能机制.pdfVIP

The Substrate-Driven Transition to an Inward-Facing Conformation in the Functional Mechanism of the Dopamine Transporter 1 3,4,5,6 1,2 1,2 Jufang Shan , Jonathan A. Javitch , Lei Shi *, Harel Weinstein * 1 Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, United States of America, 2 The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, New York, United States of America, 3 Center for Molecular Recognition, Columbia University College of Physicians and Surgeons, New York, New York, United States of America, 4 Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York, United States of America, 5 Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York, United States of America, 6 Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, New York, United States of America Abstract Background: The dopamine transporter (DAT), a member of the neurotransmitter:Na+ symporter (NSS) family, terminates dopaminergic neurotransmission and is a major molecular target for psychostimulants such as cocaine and amphetamine, and for the treatment of attention deficit disorder and depression. The crystal structures of the prokaryotic NSS homolog of DAT, the leucine transporter LeuT, have provided critical structural insights about the occluded and outward-facing conformations visited during the substrate transport, but only limited clues regarding mechanism. To understand the transport mechanism in DAT we have used a homology model based on the LeuT structure in a computational protoc