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J. Biol. Chem., Vol. 281, Issue 18, 12688-12698, May 5, 2006

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Structural and Molecular Interactions of CCR5 Inhibitors with CCR5^*

Kenji Maeda^¶, Debananda Das^¶, Hiromi Ogata-Aoki, Hirotomo Nakata, Toshikazu Miyakawa, Yasushi Tojo, Rachael Norman^¶, Yoshikazu Takaoka^||, Jianping Ding^**, Gail F. Arnold^**, Eddy Arnold^**, and Hiroaki Mitsuya^¶1

From the Department of Hematology and Department of Infectious Diseases, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Kumamoto 860-8556, Japan, the ^¶Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892, the ^||Minase Research Institute, Ono Pharmaceutical Co. Ltd., Osaka 618-8585, Japan, and the ^**Center for Advanced Biotechnology and Medicine, and Chemistry and Chemical Biology Department, Rutgers University, Piscataway, New Jersey 08854

We have characterized the structural and molecular interactions of CC-chemokine receptor 5 (CCR5) with three CCR5 inhibitors active against R5 human immunodeficiency virus type 1 (HIV-1) including the potent in vitro and in vivo CCR5 inhibitor aplaviroc (AVC). The data obtained with saturation binding assays and structural analyses delineated the key interactions responsible for the binding of CCR5 inhibitors with CCR5 and illustrated that their binding site is located in a predominantly lipophilic pocket in the interface of extracellular loops and within the upper transmembrane (TM) domain of CCR5. Mutations in the CCR5 binding sites of AVC decreased gp120 binding to CCR5 and the susceptibility to HIV-1 infection, although mutations in TM4 and TM5 that also decreased gp120 binding and HIV-1 infectivity had less effects on the binding of CC-chemokines, suggesting that CCR5 inhibition targeting appropriate regions might render the inhibition highly HIV-1-specific while preserving the CC chemokine-CCR5 interactions. The present data delineating residue by residue interactions of CCR5 with CCR5 inhibitors should not only help design more potent and more HIV-1-specific CCR5 inhibitors, but also give new insights into the dynamics of CC-chemokine-CCR5 interactions and the mechanisms of CCR5 involvement in the process of cellular entry of HIV-1.

Received for publication, November 28, 2005 , and in revised form, January 25, 2006.

^* This work was supported in part by the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health, and in part by a grant-in-aid for Scientific Research (Priority Areas) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu-Kagakusho), a Grant for Promotion of AIDS Research from the Ministry of Health, Welfare, and Labor of Japan Kosei Rohdosho H15-AIDS-001, and the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Re-emerging Infectious Diseases (Renkei Jigyo number 78, Kumamoto University) of Monbu-Kagakusho. 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.

¹ To whom correspondence should be addressed. Tel.: 81-96-373-5156; Fax: 81-96-363-5265; E-mail: hmitsuya{at}helix.nih.gov.

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