Authors: Maarten E A Reith
Publish Date: 2013/03/27
Volume: 38, Issue: 7, Pages: 1301-1302
Abstract
The study reported by Wenge and Bönisch in this issue provides critical structural information regarding extracellular loop 2 EL2 of the human norepinephrine transporter NET A systematic search among all 10 cysteine and 13 histidine residues in NET led to His222 in EL2 as the target for Nethylmaleimide its alkylation interferes with 3Hnisoxetine binding indicating the part of EL2 containing His 222 reaches back into the protein interior where it prevents access by nisoxetine to its binding site Thus EL2 in human NET does much more than conformationally assisting substrate translocation The present study underscores the importance of sitedirected mutagenesis approaches to elucidate structural features that cannot be deduced from crystals of homolog proteins In the case of NET the closest crystal structure is that of the homolog LeuT but EL2 is difficult to align with 22 less loop residues in LeuT than in NET The present results could only be achieved by the systematic mutagenesis study of all cysteines and all histidines in NET
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