ArticleBiochemistry2014
Cysteine scanning mutagenesis of transmembrane domain 10 in organic anion transporting polypeptide 1B1.
Article in Biochemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 17 citations in OpenAlex.
- Molecular Mechanisms for the Selective Transport of Dichlorofluorescein by Human Organic Anion Transporting Polypeptide 1B1.Drug metabolism and disposition: the biological fate of chemicals · 2024Article
- Rheostats, toggles, and neutrals, Oh my! A new framework for understanding how amino acid changes modulate protein function.The Journal of biological chemistry · 2024Review
- The Importance of Val386 in Transmembrane Domain 8 for the Activation of OATP1B3 by Epigallocatechin Gallate.Journal of agricultural and food chemistry · 2022Article
- Structural Plasticity Is a Feature of Rheostat Positions in the Human NaInternational journal of molecular sciences · 2022Article
- Rheostat positions: A new classification of protein positions relevant to pharmacogenomics.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2020Article
- Article
- Biodesulfurization: a model system for microbial physiology research.World journal of microbiology & biotechnology · 2016Review
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Organic anion transporting polypeptide (OATP) 1B1 is an important drug transporter expressed in human hepatocytes. Previous studies have indicated that transmembrane (TM) domain 2, 6, 8, 9, and in particular 10 might be part of the substrate binding site/translocation pathway. To explore which amino acids in TM10 are important for substrate transport, we mutated 34 amino acids individually to cysteines, expressed them in HEK293 cells, and determined their surface expression. Transport activity of the two model substrates estrone-3-sulfate and estradiol-17β-glucuronide as well as of the drug substrate valsartan for selected mutants was measured. Except for F534C and F537C, all mutants were expressed at the plasma membrane of HEK293 cells. Mutants Q541C and A549C did not transport estradiol-17β-glucuronide and showed negligible estrone-3-sulfate transport. However, A549C showed normal valsartan transport. Pretreatment with the anionic and cell impermeable sodium (2-sulfonatoethyl)methanethiosulfonate (MTSES) affected the transport of each substrate differently. Pretreatment of L545C abolished estrone-3-sulfate uptake almost completely, while it stimulated estradiol-17β-glucuronide uptake. Further analyses revealed that mutant L545C in the absence of MTSES showed biphasic kinetics for estrone-3-sulfate that was converted to monophasic kinetics with a decreased apparent affinity, explaining the previously seen inhibition. In contrast, the apparent affinity for estradiol-17β-glucuronide was not changed by MTSES treatment, but the Vmax value was increased about 4-fold, explaining the previously seen stimulation. Maleimide labeling of L545C was affected by preincubation with estrone-3-sulfate but not with estradiol-17β-glucuronide. These results strongly suggest that L545C is part of the estrone-3-sulfate binding site/translocation pathway but is not directly involved in binding/translocation of estradiol-17β-glucuronide.
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