A Three-dimensional Model of Human Organic Anion Transporter 1 AROMATIC AMINO ACIDS REQUIRED FOR SUBSTRATE TRANSPORT
作者： Jennifer L. Perry , Neetu Dembla-Rajpal , Laura A. Hall , John B. Pritchard
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摘要: Organic anion transporters (OATs) play a critical role in the handling of endogenous and exogenous organic anions by excretory barrier tissues. Little is known about OAT three-dimensional structure or substrate/protein interactions involved transport. In this investigation, theoretical model was generated for human OAT1 (hOAT1) based on fold recognition to crystal glycerol 3-phosphate transporter (GlpT) from Escherichia coli. GlpT hOAT1 share several sequence motifs as major facilitator superfamily members. The structural shows that helices 5, 7, 8, 10, 11 surround an electronegative putative active site (∼830A3). opens cytoplasm surrounded three residues not previously examined function (Tyr230 (domain 5) Lys431 Phe438 10)). Effects these p-aminohippurate (PAH) cidofovir transport were assessed point mutations Xenopus oocyte expression system. Membrane protein severely limited Y230A mutant. For K431A F438A mutants, [3H]PAH uptake less than 30% wild-type after correction. Reduced Vmax values mutant confirmed lower expression. addition, exhibited increased affinity but significantly different PAH. Differences PAH also observed Y230F determined cidofovir, whereas similar hOAT1. Therefore, has identified two new residues, Tyr230 Phe438, which are important interactions.
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