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Molecular Pharmacology

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Research ArticleArticle

Conserved Tryptophan Residues within Putative Transmembrane Domain 6 Affect Transport Function of Organic Anion Transporting Polypeptide 1B1

Jiujiu Huang, Nan Li, Weifang Hong, Kai Zhan, Xuan Yu, Hong Huang and Mei Hong
Molecular Pharmacology October 2013, 84 (4) 521-527; DOI: https://doi.org/10.1124/mol.113.085977
Jiujiu Huang
College of Life Science, South China Agricultural University, Guangzhou, China (J.H., N.L., W.H., K.Z., X.Y., M.H.); and School of Information, University of South Florida, Tampa, Florida (H.H.)
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Nan Li
College of Life Science, South China Agricultural University, Guangzhou, China (J.H., N.L., W.H., K.Z., X.Y., M.H.); and School of Information, University of South Florida, Tampa, Florida (H.H.)
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Weifang Hong
College of Life Science, South China Agricultural University, Guangzhou, China (J.H., N.L., W.H., K.Z., X.Y., M.H.); and School of Information, University of South Florida, Tampa, Florida (H.H.)
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Kai Zhan
College of Life Science, South China Agricultural University, Guangzhou, China (J.H., N.L., W.H., K.Z., X.Y., M.H.); and School of Information, University of South Florida, Tampa, Florida (H.H.)
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Xuan Yu
College of Life Science, South China Agricultural University, Guangzhou, China (J.H., N.L., W.H., K.Z., X.Y., M.H.); and School of Information, University of South Florida, Tampa, Florida (H.H.)
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Hong Huang
College of Life Science, South China Agricultural University, Guangzhou, China (J.H., N.L., W.H., K.Z., X.Y., M.H.); and School of Information, University of South Florida, Tampa, Florida (H.H.)
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Mei Hong
College of Life Science, South China Agricultural University, Guangzhou, China (J.H., N.L., W.H., K.Z., X.Y., M.H.); and School of Information, University of South Florida, Tampa, Florida (H.H.)
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Abstract

The organic anion-transporting polypeptides (OATPs, gene symbol SLCO) are a family of transporters that play important roles in the absorption, distribution, metabolism, and excretion of various drugs. Although substrate specificity of transporter proteins is under extensive study, the underlying mechanisms for substrate binding and/or recognition remain largely unknown. Transmembrane domain 6 (TM6) is a relatively conserved region within OATP family members, and several amino acid residues on its extracellular half are part of the OATP family signature sequence D-X-RW-(I,V)-GAWWX-G-(F,L)-L. In the present study, two adjacent tryptophan residues (Trp258 and Trp259) within TM6 were identified as critical amino acids for the transport function of OATP1B1. Kinetic studies showed that substitution of Trp258 with alanine resulted in monophasic kinetics for estrone-3-sulfate uptake, with a significantly higher Km value (Km = 12.0 ± 2.8 μM) than the high-affinity component of wild-type OATP1B1 (Km = 0.38 ± 0.06 μM). On the other hand, W259A retained the biphasic characteristic of the transporter. Km values of the high- and low-affinity components for estrone-3-sulfate of W259A are 1.93 ± 0.76 μM and 30.8 ± 4.4 μM, respectively. Further studies revealed that W258A retained transport function of another prototypic substrate, taurocholate, while W259A displayed a dramatically reduced uptake of the substrate and exhibited an 8-fold increase in the Km value compared with that of the wild-type and W258A. Our results suggest that Trp258 and Trp259 may play different roles in the uptake of different substrates by OATP1B1.

Footnotes

    • Received March 2, 2013.
    • Accepted July 15, 2013.
  • J.H. and N.L. contributed equally to this work.

  • This work was supported by the Guangdong Province Talent Introduction Project [Grant 2009]; and the National Natural Science Foundation of China [Grant 81141115] (to M.H.).

  • dx.doi.org/10.1124/mol.113.085977.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 84 (4)
Molecular Pharmacology
Vol. 84, Issue 4
1 Oct 2013
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Research ArticleArticle

Roles of Conserved Tryptophan Residues in TM6 of OATP1B1

Jiujiu Huang, Nan Li, Weifang Hong, Kai Zhan, Xuan Yu, Hong Huang and Mei Hong
Molecular Pharmacology October 1, 2013, 84 (4) 521-527; DOI: https://doi.org/10.1124/mol.113.085977

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Research ArticleArticle

Roles of Conserved Tryptophan Residues in TM6 of OATP1B1

Jiujiu Huang, Nan Li, Weifang Hong, Kai Zhan, Xuan Yu, Hong Huang and Mei Hong
Molecular Pharmacology October 1, 2013, 84 (4) 521-527; DOI: https://doi.org/10.1124/mol.113.085977
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