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      The NSAID allosteric site of human cytosolic sulfotransferases

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          Abstract

          Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed drugs worldwide—more than 111 million prescriptions were written in the United States in 2014. NSAIDs allosterically inhibit cytosolic sulfotransferases (SULTs) with high specificity and therapeutically relevant affinities. This study focuses on the interactions of SULT1A1 and mefenamic acid (MEF)—a potent, highly specific NSAID inhibitor of 1A1. Here, the first structure of an NSAID allosteric site—the MEF-binding site of SULT1A1—is determined using spin-label triangulation NMR. The structure is confirmed by site-directed mutagenesis and provides a molecular framework for understanding NSAID binding and isoform specificity. The mechanism of NSAID inhibition is explored using molecular dynamics and equilibrium and pre-steady-state ligand-binding studies. MEF inhibits SULT1A1 turnover through an indirect (helix-mediated) stabilization of the closed form of the active-site cap of the enzyme, which traps the nucleotide and slows its release. Using the NSAID-binding site structure of SULT1A1 as a comparative model, it appears that 11 of the 13 human SULT isoforms harbor an NSAID-binding site. We hypothesize that these sites evolved to enable SULT isoforms to respond to metabolites that lie within their metabolic domains. Finally, the NSAID-binding site structure offers a template for developing isozyme-specific allosteric inhibitors that can be used to regulate specific areas of sulfuryl-transfer metabolism.

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          Author and article information

          Journal
          J Biol Chem
          J. Biol. Chem
          jbc
          jbc
          JBC
          The Journal of Biological Chemistry
          American Society for Biochemistry and Molecular Biology (11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A. )
          0021-9258
          1083-351X
          8 December 2017
          16 October 2017
          : 292
          : 49
          : 20305-20312
          Affiliations
          From the Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461-1926
          Author notes
          [1 ] To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461-1926. Tel.: 718-430-2857; Fax: 718-430-8711; E-mail: tom.leyh@ 123456einstein.yu.edu .

          Edited by Wolfgang Peti

          Article
          PMC5724015 PMC5724015 5724015 M117.817387
          10.1074/jbc.M117.817387
          5724015
          29038294
          © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
          Funding
          Funded by: National Institutes of Health , open-funder-registry 10.13039/100000002;
          Award ID: GM121849
          Award ID: GM106158
          Categories
          Enzymology

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