LeuT, it was possible to
understand better how neurotransmitters bind to their respective transporter.
Due to the fact that the LeuT amino acid sequence is only 25%
similar to the one of BATs the findings cannot help directly in the development
of therapeutical agents. This difference in structure can be observed
when SSRIs and TCAs bind to the extracellular vestibule of LeuT and act as
non-competitive inhibitors. On the other hand the same molecules behave as
competitive inhibitors when they interact with eukaryotic BATs.
The difference in affinity of BATs and LeuT was overcome by genetically engineering the LeuT protein by mutating key residues found in the primary binding pocket which are involved in substrate binding. LeuT was then able to bind to BAT forming the LeuBAT mutant which has a high affinity for SSRIs, SNRIs and TCAs. Then, the genetically modified LeuBAT would act as a suitable model for figuring out the mechanism of inhibitors and antidepressants functioning on human BAT.
The difference in affinity of BATs and LeuT was overcome by genetically engineering the LeuT protein by mutating key residues found in the primary binding pocket which are involved in substrate binding. LeuT was then able to bind to BAT forming the LeuBAT mutant which has a high affinity for SSRIs, SNRIs and TCAs. Then, the genetically modified LeuBAT would act as a suitable model for figuring out the mechanism of inhibitors and antidepressants functioning on human BAT.
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