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Titolo:
Delineating structure-function relationships in the dopamine transporter from natural and engineered Zn2+ binding sites
Autore:
Gether, U; Norregaard, L; Loland, CJ;
Indirizzi:
Univ Copenhagen, Panum Inst 12 5 22, Dept Med Physiol, Div Cellular & Mol Physiol, DK-2200 Copenhagen N, Denmark Univ Copenhagen Copenhagen DenmarkN siol, DK-2200 Copenhagen N, Denmark
Titolo Testata:
LIFE SCIENCES
fascicolo: 19-20, volume: 68, anno: 2001,
pagine: 2187 - 2198
SICI:
0024-3205(20010406)68:19-20<2187:DSRITD>2.0.ZU;2-K
Fonte:
ISI
Lingua:
ENG
Soggetto:
TACHYKININ NK-1 RECEPTOR; SEROTONIN TRANSPORTER; TRANSMEMBRANE DOMAIN; NEUROTRANSMITTER TRANSPORTERS; NOREPINEPHRINE TRANSPORTERS; COCAINE BINDING; AMINO-ACID; ZINC IONS; RECOGNITION; MODULATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
49
Recensione:
Indirizzi per estratti:
Indirizzo: Gether, U Univ Copenhagen, Panum Inst 12 5 22, Dept Med Physiol, Div Cellular & Mol Physiol, DK-2200 Copenhagen N, Denmark Univ Copenhagen Copenhagen Denmark N 200 Copenhagen N, Denmark
Citazione:
U. Gether et al., "Delineating structure-function relationships in the dopamine transporter from natural and engineered Zn2+ binding sites", LIFE SCI, 68(19-20), 2001, pp. 2187-2198

Abstract

The dopamine transporter is member of a large family of Na+/Cl- dependent neurotransmitter and amino acid transporters, Little is known about the molecular basis for substrate translocation in this class of transporters as well as their tertiary structure remains elusive. In this report, we providethe first crude insight into the structural organization of the human dopamine transporter (hDAT) based on the identification of an endogenous high affinity Zn2+ binding site followed by engineering of an artificial Zn2+ binding site. By binding to the endogenous site, Zn2+ acts as a potent non-competitive inhibitor of dopamine uptake mediated by the hDAT transiently expressed in COS-7 cells. Systematic mutagenesis of potential Zn2+ coordinatingresidues lead to the identification of three residues on the predicted extracellular face of the transporter, (193)His in the second extracellular loop, (375)His at the external end of the putative transmembrane segment (TM)7, and (396)Glu at the external end of TM 8, forming three coordinates in the endogenous Zn2+ binding site. The three residues are separate in the primary structure but their common participation in binding the small Zn(II) ion define their spatial proximity in the tertiary structure of the transporter. Finally, an artificial inhibitory Zn2+ binding site was engineered between TM 7 and TM 8. This binding site both verify the proximity between the two domains as wells as it supports an a-helical configuration at the topof TM 8 in the hDAT. (C) 2001 Elsevier Science Inc. All rights reserved.

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Documento generato il 28/11/20 alle ore 04:35:10