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Predictions of CCR1 Chemokine Receptor Structure and BX 471 Antagonist Binding Followed by Experimental Validation

Vaidehi, Nagarajan and Schyler, Sabine and Trabanino, Rene J. and Floriano, Wely B. and Abrol, Ravinder and Sharma, Shantanu and Kochanny, Monica and Koovakat, Sunil and Dunning, Laura and Liang, Meina and Fox, James M. and Mendonça, Filipa and Pease, James E. and Goddard, William A., III and Horuk, Richard (2006) Predictions of CCR1 Chemokine Receptor Structure and BX 471 Antagonist Binding Followed by Experimental Validation. Journal of Biological Chemistry, 281 (37). pp. 27613-27620. ISSN 0021-9258. doi:10.1074/jbc.M601389200.

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A major challenge in the application of structure-based drug design methods to proteins belonging to the superfamily of G protein-coupled receptors (GPCRs) is the paucity of structural information (1). The 19 chemokine receptors, belonging to the Class A family of GPCRs, are important drug targets not only for autoimmune diseases like multiple sclerosis but also for the blockade of human immunodeficiency virus type 1 entry (2). Using the MembStruk computational method (3), we predicted the three-dimensional structure of the human CCR1 receptor. In addition, we predicted the binding site of the small molecule CCR1 antagonist BX 471, which is currently in Phase II clinical trials (4). Based on the predicted antagonist binding site we designed 17 point mutants of CCR1 to validate the predictions. Subsequent competitive ligand binding and chemotaxis experiments with these mutants gave an excellent correlation to these predictions. In particular, we find that Tyr-113 and Tyr-114 on transmembrane domain 3 and Ile-259 on transmembrane 6 contribute significantly to the binding of BX 471. Finally, we used the predicted and validated structure of CCR1 in a virtual screening validation of the Maybridge data base, seeded with selective CCR1 antagonists. The screen identified 63% of CCR1 antagonists in the top 5% of the hits. Our results indicate that rational drug design for GPCR targets is a feasible approach.

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Abrol, Ravinder0000-0001-7333-6793
Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2006 the American Society for Biochemistry and Molecular Biology. Received for publication, February 14, 2006 , and in revised form, July 12, 2006. Originally published In Press as doi:10.1074/jbc.M601389200 on July 12, 2006 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.
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Issue or Number:37
Record Number:CaltechAUTHORS:VAIjbc06
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ID Code:5124
Deposited By: Archive Administrator
Deposited On:02 Oct 2006
Last Modified:08 Nov 2021 20:22

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