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Research ArticleArticle

Identification and Pharmacological Characterization of Multiple Allosteric Binding Sites on the Free Fatty Acid 1 Receptor

Daniel C.-H. Lin, Qi Guo, Jian Luo, Jane Zhang, Kathy Nguyen, Michael Chen, Thanh Tran, Paul J. Dransfield, Sean P. Brown, Jonathan Houze, Marc Vimolratana, Xian Yun Jiao, Yingcai Wang, Nigel J. M. Birdsall and Gayathri Swaminath
Molecular Pharmacology November 2012, 82 (5) 843-859; DOI: https://doi.org/10.1124/mol.112.079640
Daniel C.-H. Lin
Amgen Inc., South San Francisco, California (D.C.-H.L., Q.G., J.L., J.Z., K.N., M.C., T.T., P.J.D., S.P.B., J.H., M.V., X.Y.J., Y.W., G.S.); and Division of Physical Biochemistry, MRC National Institute for Medical Research, London, United Kingdom (N.J.M.B.)
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Qi Guo
Amgen Inc., South San Francisco, California (D.C.-H.L., Q.G., J.L., J.Z., K.N., M.C., T.T., P.J.D., S.P.B., J.H., M.V., X.Y.J., Y.W., G.S.); and Division of Physical Biochemistry, MRC National Institute for Medical Research, London, United Kingdom (N.J.M.B.)
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Jian Luo
Amgen Inc., South San Francisco, California (D.C.-H.L., Q.G., J.L., J.Z., K.N., M.C., T.T., P.J.D., S.P.B., J.H., M.V., X.Y.J., Y.W., G.S.); and Division of Physical Biochemistry, MRC National Institute for Medical Research, London, United Kingdom (N.J.M.B.)
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Jane Zhang
Amgen Inc., South San Francisco, California (D.C.-H.L., Q.G., J.L., J.Z., K.N., M.C., T.T., P.J.D., S.P.B., J.H., M.V., X.Y.J., Y.W., G.S.); and Division of Physical Biochemistry, MRC National Institute for Medical Research, London, United Kingdom (N.J.M.B.)
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Kathy Nguyen
Amgen Inc., South San Francisco, California (D.C.-H.L., Q.G., J.L., J.Z., K.N., M.C., T.T., P.J.D., S.P.B., J.H., M.V., X.Y.J., Y.W., G.S.); and Division of Physical Biochemistry, MRC National Institute for Medical Research, London, United Kingdom (N.J.M.B.)
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Michael Chen
Amgen Inc., South San Francisco, California (D.C.-H.L., Q.G., J.L., J.Z., K.N., M.C., T.T., P.J.D., S.P.B., J.H., M.V., X.Y.J., Y.W., G.S.); and Division of Physical Biochemistry, MRC National Institute for Medical Research, London, United Kingdom (N.J.M.B.)
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Thanh Tran
Amgen Inc., South San Francisco, California (D.C.-H.L., Q.G., J.L., J.Z., K.N., M.C., T.T., P.J.D., S.P.B., J.H., M.V., X.Y.J., Y.W., G.S.); and Division of Physical Biochemistry, MRC National Institute for Medical Research, London, United Kingdom (N.J.M.B.)
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Paul J. Dransfield
Amgen Inc., South San Francisco, California (D.C.-H.L., Q.G., J.L., J.Z., K.N., M.C., T.T., P.J.D., S.P.B., J.H., M.V., X.Y.J., Y.W., G.S.); and Division of Physical Biochemistry, MRC National Institute for Medical Research, London, United Kingdom (N.J.M.B.)
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Sean P. Brown
Amgen Inc., South San Francisco, California (D.C.-H.L., Q.G., J.L., J.Z., K.N., M.C., T.T., P.J.D., S.P.B., J.H., M.V., X.Y.J., Y.W., G.S.); and Division of Physical Biochemistry, MRC National Institute for Medical Research, London, United Kingdom (N.J.M.B.)
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Jonathan Houze
Amgen Inc., South San Francisco, California (D.C.-H.L., Q.G., J.L., J.Z., K.N., M.C., T.T., P.J.D., S.P.B., J.H., M.V., X.Y.J., Y.W., G.S.); and Division of Physical Biochemistry, MRC National Institute for Medical Research, London, United Kingdom (N.J.M.B.)
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Marc Vimolratana
Amgen Inc., South San Francisco, California (D.C.-H.L., Q.G., J.L., J.Z., K.N., M.C., T.T., P.J.D., S.P.B., J.H., M.V., X.Y.J., Y.W., G.S.); and Division of Physical Biochemistry, MRC National Institute for Medical Research, London, United Kingdom (N.J.M.B.)
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Xian Yun Jiao
Amgen Inc., South San Francisco, California (D.C.-H.L., Q.G., J.L., J.Z., K.N., M.C., T.T., P.J.D., S.P.B., J.H., M.V., X.Y.J., Y.W., G.S.); and Division of Physical Biochemistry, MRC National Institute for Medical Research, London, United Kingdom (N.J.M.B.)
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Yingcai Wang
Amgen Inc., South San Francisco, California (D.C.-H.L., Q.G., J.L., J.Z., K.N., M.C., T.T., P.J.D., S.P.B., J.H., M.V., X.Y.J., Y.W., G.S.); and Division of Physical Biochemistry, MRC National Institute for Medical Research, London, United Kingdom (N.J.M.B.)
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Nigel J. M. Birdsall
Amgen Inc., South San Francisco, California (D.C.-H.L., Q.G., J.L., J.Z., K.N., M.C., T.T., P.J.D., S.P.B., J.H., M.V., X.Y.J., Y.W., G.S.); and Division of Physical Biochemistry, MRC National Institute for Medical Research, London, United Kingdom (N.J.M.B.)
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Gayathri Swaminath
Amgen Inc., South San Francisco, California (D.C.-H.L., Q.G., J.L., J.Z., K.N., M.C., T.T., P.J.D., S.P.B., J.H., M.V., X.Y.J., Y.W., G.S.); and Division of Physical Biochemistry, MRC National Institute for Medical Research, London, United Kingdom (N.J.M.B.)
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Abstract

Activation of FFA1 (GPR40), a member of G protein-coupling receptor family A, is mediated by medium- and long-chain fatty acids and leads to amplification of glucose-stimulated insulin secretion, suggesting a potential role for free fatty acid 1 (FFA1) as a target for type 2 diabetes. It was assumed previously that there is a single binding site for fatty acids and synthetic FFA1 agonists. However, using members of two chemical series of partial and full agonists that have been identified, radioligand binding interaction studies revealed that the full agonists do not bind to the same site as the partial agonists but exhibit positive heterotropic cooperativity. Analysis of functional data reveals positive functional cooperativity between the full agonists and partial agonists in various functional assays (in vitro and ex vivo) and also in vivo. Furthermore, the endogenous fatty acid docosahexaenoic acid (DHA) shows negative or neutral cooperativity with members of both series of agonists in binding assays but displays positive cooperativity in functional assays. Another synthetic agonist is allosteric with members of both agonist series, but apparently competitive with DHA. Therefore, there appear to be three allosterically linked binding sites on FFA1 with agonists specific for each of these sites. Activation of free fatty acid 1 receptor (FFAR1) by each of these agonists is differentially affected by mutations of two arginine residues, previously found to be important for FFAR1 binding and activation. These ligands with their high potencies and strong positive functional cooperativity with endogenous fatty acids, demonstrated in vitro and in vivo, have the potential to deliver therapeutic benefits.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • The work was supported in part by the Medical Research Council, United Kingdom [Grant U117532193].

  • N.J.M.B. has been a paid consultant for AMGEN Inc.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.079640.

  • ABBREVIATIONS:

    FFA
    free fatty acid
    GPC
    G protein-coupled fatty acid receptor
    TAK-875
    [(3S)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate
    AMG 837
    (S)-3(-4-((4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl) methoxy) phenyl)hex-4-ynoic acid
    DHA
    docosahexaenoic acid
    FFAR1
    free fatty acid receptor 1
    AM 1638
    (S)-3-cyclopropyl-3-(3-((2-(5,5-dimethylcyclopent-1-en-1-yl)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-ylmethoxy) phenyl)propanoic acid
    AM 8182
    (S,E)-3-(4-((2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)methoxy)phenyl)hex-4-enoic acid)
    AM 6331
    (S)-3-(4-((4′-chloro-2′-ethoxy-[1,1′-biphenyl]-4-yl)methoxy phenyl)hex-4-ynoic acid
    HBSS
    Hanks' buffered salt solution
    ERK
    extracellular signal-regulated kinase
    BSA
    bovine serum albumin
    HSA
    human serum albumin
    CHO
    Chinese hamster ovary
    hFFA
    human FFA
    FACS
    fluorescence-activated cell sorting
    STZ
    streptozotocin
    IP
    inositol phosphate
    SAR
    structure-activity relationship
    GPCR
    G protein-coupled receptor
    LA
    α-linolenic acid
    HF/STZ
    high-fat STZ-treated
    ANOVA
    analysis of variance
    GW9508
    4-[[(3-phenoxyphenyl)methyl]amino]benzenepropanoic acid.

  • Received April 26, 2012.
  • Accepted August 2, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (5)
Molecular Pharmacology
Vol. 82, Issue 5
1 Nov 2012
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Research ArticleArticle

Allosteric Binding Sites on the FFA1 Receptor

Daniel C.-H. Lin, Qi Guo, Jian Luo, Jane Zhang, Kathy Nguyen, Michael Chen, Thanh Tran, Paul J. Dransfield, Sean P. Brown, Jonathan Houze, Marc Vimolratana, Xian Yun Jiao, Yingcai Wang, Nigel J. M. Birdsall and Gayathri Swaminath
Molecular Pharmacology November 1, 2012, 82 (5) 843-859; DOI: https://doi.org/10.1124/mol.112.079640

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Research ArticleArticle

Allosteric Binding Sites on the FFA1 Receptor

Daniel C.-H. Lin, Qi Guo, Jian Luo, Jane Zhang, Kathy Nguyen, Michael Chen, Thanh Tran, Paul J. Dransfield, Sean P. Brown, Jonathan Houze, Marc Vimolratana, Xian Yun Jiao, Yingcai Wang, Nigel J. M. Birdsall and Gayathri Swaminath
Molecular Pharmacology November 1, 2012, 82 (5) 843-859; DOI: https://doi.org/10.1124/mol.112.079640
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