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J. Biol. Chem., Vol. 282, Issue 33, 23841-23853, August 17, 2007

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Structural Variation Governs Substrate Specificity for Organic Anion Transporter (OAT) Homologs

POTENTIAL REMOTE SENSING BY OAT FAMILY MEMBERS^*

Gregory Kaler, David M. Truong, Akash Khandelwal, Megha Nagle, Satish A. Eraly, Peter W. Swaan, and Sanjay K. Nigam^¶||1

From the Departments of Medicine, ^¶Pediatrics, and ^||Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093 and the Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201

Organic anion transporters (OATs, SLC22) interact with a remarkably diverse array of endogenous and exogenous organic anions. However, little is known about the structural features that determine their substrate selectivity. We examined the substrate binding preferences and transport function of olfactory organic anion transporter, Oat6, in comparison with the more broadly expressed transporter, Oat1 (first identified as NKT). In analyzing interactions of both transporters with over 40 structurally diverse organic anions, we find a correlation between organic anion potency (pK_i) and hydrophobicity (logP) suggesting a hydrophobicity-driven association with transporter-binding sites, which appears particularly prominent for Oat6. On the other hand, organic anion binding selectivity between Oat6 and Oat1 is influenced by the anion mass and net charge. Smaller mono-anions manifest greater potency for Oat6 and di-anions for Oat1. Comparative molecular field analysis confirms these mechanistic insights and provides a model for predicting new OAT substrates. By comparative molecular field analysis, both hydrophobic and charged interactions contribute to Oat1 binding, although it is predominantly the former that contributes to Oat6 binding. Together, the data suggest that, although the three-dimensional structures of these two transporters may be very similar, the binding pockets exhibit crucial differences. Furthermore, for six radiolabeled substrates, we assessed transport efficacy (V_max) for Oat6 and Oat1. Binding potency and transport efficacy had little correlation, suggesting that different molecular interactions are involved in substrate binding to the transporter and translocation across the membrane. Substrate specificity for a particular transporter may enable design of drugs for targeting to specific tissues (e.g. olfactory mucosa). We also discuss how these data suggest a possible mechanism for remote sensing between OATs in different tissue compartments (e.g. kidney, olfactory mucosa) via organic anions.

Received for publication, April 25, 2007 , and in revised form, June 5, 2007.

^* This work was supported by National Institutes of Health Grants AI057695, HD40011 (to S. K. N.), DK61425 (to P. W. S.), DK064839, and DK075486 (to S. A. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1.

¹ To whom correspondence should be addressed: University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093.

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