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Research ArticleArticle

Structural and Functional Analysis of G Protein–Coupled Receptor Kinase Inhibition by Paroxetine and a Rationally Designed Analog

Kristoff T. Homan, Emily Wu, Michael W. Wilson, Puja Singh, Scott D. Larsen and John J. G. Tesmer
Molecular Pharmacology February 2014, 85 (2) 237-248; DOI: https://doi.org/10.1124/mol.113.089631
Kristoff T. Homan
Life Sciences Institute and the Departments of Pharmacology and Biological Sciences (K.T.H., E.W., P.S., J.J.G.T.), and Vahlteich Medicinal Chemistry Core and the Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan (M.W.W., S.D.L.)
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Emily Wu
Life Sciences Institute and the Departments of Pharmacology and Biological Sciences (K.T.H., E.W., P.S., J.J.G.T.), and Vahlteich Medicinal Chemistry Core and the Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan (M.W.W., S.D.L.)
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Michael W. Wilson
Life Sciences Institute and the Departments of Pharmacology and Biological Sciences (K.T.H., E.W., P.S., J.J.G.T.), and Vahlteich Medicinal Chemistry Core and the Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan (M.W.W., S.D.L.)
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Puja Singh
Life Sciences Institute and the Departments of Pharmacology and Biological Sciences (K.T.H., E.W., P.S., J.J.G.T.), and Vahlteich Medicinal Chemistry Core and the Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan (M.W.W., S.D.L.)
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Scott D. Larsen
Life Sciences Institute and the Departments of Pharmacology and Biological Sciences (K.T.H., E.W., P.S., J.J.G.T.), and Vahlteich Medicinal Chemistry Core and the Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan (M.W.W., S.D.L.)
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John J. G. Tesmer
Life Sciences Institute and the Departments of Pharmacology and Biological Sciences (K.T.H., E.W., P.S., J.J.G.T.), and Vahlteich Medicinal Chemistry Core and the Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan (M.W.W., S.D.L.)
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Abstract

Recently we identified the serotonin reuptake inhibitor paroxetine as an inhibitor of G protein–coupled receptor kinase 2 (GRK2) that improves cardiac performance in live animals. Paroxetine exhibits up to 50-fold selectivity for GRK2 versus other GRKs. A better understanding of the molecular basis of this selectivity is important for the development of even more selective and potent small molecule therapeutics and chemical genetic probes. We first sought to understand the molecular mechanisms underlying paroxetine selectivity among GRKs. We directly measured the KD for paroxetine and assessed its mechanism of inhibition for each of the GRK subfamilies and then determined the atomic structure of its complex with GRK1, the most weakly inhibited GRK tested. Our results suggest that the selectivity of paroxetine for GRK2 largely reflects its lower affinity for adenine nucleotides. Thus, stabilization of off-pathway conformational states unique to GRK2 will likely be key for the development of even more selective inhibitors. Next, we designed a benzolactam derivative of paroxetine that has optimized interactions with the hinge of the GRK2 kinase domain. The crystal structure of this compound in complex with GRK2 confirmed the predicted interactions. Although the benzolactam derivative did not significantly alter potency of inhibition among GRKs, it exhibited 20-fold lower inhibition of serotonin reuptake. However, there was an associated increase in the potency for inhibition of other AGC kinases, suggesting that the unconventional hydrogen bond formed by the benzodioxole ring of paroxetine is better accommodated by GRKs.

Footnotes

    • Received September 17, 2013.
    • Accepted November 11, 2013.
  • This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants HL071818 and HL086865] to J.J.G.T.; and the American Heart Association [Grant N014938] to K.T.H. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357; and use of LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and Michigan Technology Tri-Corridor Grant [085P1000817].

  • dx.doi.org/10.1124/mol.113.089631.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 85 (2)
Molecular Pharmacology
Vol. 85, Issue 2
1 Feb 2014
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Research ArticleArticle

Inhibition of GRKs by Paroxetine Analogs

Kristoff T. Homan, Emily Wu, Michael W. Wilson, Puja Singh, Scott D. Larsen and John J. G. Tesmer
Molecular Pharmacology February 1, 2014, 85 (2) 237-248; DOI: https://doi.org/10.1124/mol.113.089631

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Research ArticleArticle

Inhibition of GRKs by Paroxetine Analogs

Kristoff T. Homan, Emily Wu, Michael W. Wilson, Puja Singh, Scott D. Larsen and John J. G. Tesmer
Molecular Pharmacology February 1, 2014, 85 (2) 237-248; DOI: https://doi.org/10.1124/mol.113.089631
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