Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, and Department of Cell Biology, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
Curr Opin Struct Biol. 2010 Aug;20(4):415-22. doi: 10.1016/j.sbi.2010.05.007. Epub 2010 Jun 16.
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.
LeuT 是神经递质/钠离子转运体家族的成员之一，该家族包括血清素、去甲肾上腺素和多巴胺的神经元转运体。LeuT 的原始晶体结构显示蛋白质中心有一个主要的亮氨酸结合位点。LeuT 被不同类别的抗抑郁药抑制，这些药物是血清素转运体的有效抑制剂。新确定的 LeuT-抗抑郁药复合物的晶体结构为研究血清素转运体中的药物结合提供了机会，而其确切位置仍存在争议。LeuT-色氨酸复合物的结构显示与主要底物结合位点重叠的结合位点。最近发现了一个次要的底物结合位点，其中亮氨酸的结合触发了细胞质中主要底物的释放。这种双结合位点模型为更好地理解药物结合和哺乳动物转运体的抑制机制提供了机会。
