Substrate and drug binding sites in LeuT
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- 作者：Ajeeta Nyola ; Nathan K Karpowich ; Juan Zhen ; Jennifer Marden ; Maarten E Reith ; Da-Neng Wang
- 刊名：Current Opinion in Structural Biology
- 出版年：2010
- 出版时间：August 2010
- 年：2010
- 卷：20
- 期：4
- 页码：415-422
- 全文大小：423 K
文摘
LeuT is a member of the neurotransmitter/sodium symporter family, which includes the neuronal transporters for serotonin, norepinephrine, and dopamine. The original crystal structure of LeuT shows a primary leucine-binding site at the center of the protein. LeuT is inhibited by different classes of antidepressants that act as potent inhibitors of the serotonin transporter. The newly determined crystal structures of LeuT–antidepressant complexes provide opportunities to probe drug binding in the serotonin transporter, of which the exact position remains controversial. Structure of a LeuT–tryptophan complex shows an overlapping binding site with the primary substrate site. A secondary substrate binding site was recently identified, where the binding of a leucine triggers the cytoplasmic release of the primary substrate. This two binding site model presents opportunities for a better understanding of drug binding and the mechanism of inhibition for mammalian transporters.