{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T08:08:30Z","timestamp":1776845310874,"version":"3.51.2"},"reference-count":48,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2009,8,31]],"date-time":"2009-08-31T00:00:00Z","timestamp":1251676800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Proteins"],"published-print":{"date-parts":[[2010,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The dopamine transporter (DAT) operates via facilitated diffusion, harnessing an inward Na<jats:sup>+<\/jats:sup>gradient to drive dopamine from the extracellular synaptic cleft to the neuron interior. The DAT is relevant to central nervous system disorders such as Parkinson disease and attention\u2010deficit hyperactivity disorder and is the primary site of action for the abused psychostimulants cocaine and amphetamines. Crystallization of a DAT homolog, the bacterial leucine transporter LeuT, provided the first reliable 3\u2010D DAT template. Here, the LeuT crystal structure and the DAT molecular model have been combined with their respective substrates, leucine and dopamine, in lipid bilayer molecular dynamics simulations toward tracking substrate movement along the protein's substrate\/ion permeation pathway. Specifically, movement of residue pairs that comprise the \u201cexternal gate\u201d was followed as a function of substrate presence. The transmembrane (TM) 1 arginine\u2010TM 10 aspartate strut formed less readily in DAT compared with LeuT, with or without substrate present. For LeuT but not DAT, the addition of substrate enhanced the chances of forming the TM 1\u201010 bridge. Also, movement of the fourth extracellular loop EL\u20104 in the presence of substrate was more pronounced for DAT, the EL\u20104 unwinding to a degree. The overall similarity between the LeuT and DAT molecular dynamics simulations indicated that LeuT was a legitimate model to guide DAT structure\u2010function predictions. There were, nevertheless, differences significant enough to allow for DAT\u2010unique insights, which may include how cocaine, methylphenidate (Ritalin, NIDA Drug Supply, Rockville, MD), and other DAT blockers are not recognized as substrates even though they can access the primary substrate binding pocket. Proteins 2010. \u00a9 2009 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/prot.22601","type":"journal-article","created":{"date-parts":[[2009,8,31]],"date-time":"2009-08-31T20:10:36Z","timestamp":1251749436000},"page":"797-811","source":"Crossref","is-referenced-by-count":37,"title":["Molecular dynamics of leucine and dopamine transporter proteins in a model cell membrane lipid bilayer"],"prefix":"10.1002","volume":"78","author":[{"given":"Patrick C.","family":"Gedeon","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mart\u00edn","family":"Indarte","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher K.","family":"Surratt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffry D.","family":"Madura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,11,6]]},"reference":[{"key":"e_1_2_5_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF03033354"},{"key":"e_1_2_5_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.alcohol.2006.12.005"},{"key":"e_1_2_5_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/1531-8257(200101)16:1<124::AID-MDS1007>3.0.CO;2-R"},{"key":"e_1_2_5_5_2","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.158.11.1843"},{"key":"e_1_2_5_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9861(20000501)420:2<211::AID-CNE5>3.0.CO;2-3"},{"key":"e_1_2_5_7_2","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0022-3565(25)31549-1","article-title":"Chemical release of dopamine from striatal homogenates: evidence for an exchange diffusion model","volume":"208","author":"Fischer JF","year":"1979","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_5_8_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.47.120505.105140"},{"key":"e_1_2_5_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2820058"},{"key":"e_1_2_5_10_2","first-page":"E739","article-title":"Recognition of psychostimulants, antidepressants, and other inhibitors of synaptic neurotransmitter uptake by the plasma membrane monoamine transporters","volume":"7","author":"Surratt CK","year":"2005","journal-title":"Am Assoc Pharmaceu Sci J"},{"key":"e_1_2_5_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-59259-470-2_3"},{"key":"e_1_2_5_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2003.08.052"},{"key":"e_1_2_5_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2003.08.068"},{"key":"e_1_2_5_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03978"},{"key":"e_1_2_5_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr078246a"},{"key":"e_1_2_5_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb0907-792"},{"key":"e_1_2_5_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0705600104"},{"key":"e_1_2_5_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature06133"},{"key":"e_1_2_5_19_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.106.026120"},{"key":"e_1_2_5_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2006.03.002"},{"key":"e_1_2_5_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.200600243"},{"key":"e_1_2_5_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja076403h"},{"key":"e_1_2_5_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.21598"},{"key":"e_1_2_5_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2008.05.008"},{"key":"e_1_2_5_25_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1166777"},{"key":"e_1_2_5_26_2","article-title":"Comparative molecular modeling of the dopamine transporter using the leucine transporter LeuTAa as a template","author":"Indarte M","year":"2006","journal-title":"Soc Neurosci"},{"key":"e_1_2_5_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2146"},{"key":"e_1_2_5_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature06038"},{"key":"e_1_2_5_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1147614"},{"key":"e_1_2_5_30_2","doi-asserted-by":"publisher","DOI":"10.1021\/cb7001818"},{"key":"e_1_2_5_31_2","unstructured":"Chemical Computing Group.Molecular Operative Environment (MOE) 2008.10. 1255 University Street Suite 1600 Montreal Quebec Canada H3B 3X3.2008."},{"key":"e_1_2_5_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.540040211"},{"key":"e_1_2_5_33_2","first-page":"271","volume-title":"CHARMM: the energy function and its parameterization with an overview of the program (vol 1). 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