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Analysis of binding sites for the new small-molecule CCR5 antagonist TAK-220 on human CCR5.


ABSTRACT: G protein-coupled receptor CCR5 is the main coreceptor for macrophage-tropic human immunodeficiency virus type 1 (HIV-1), and various small-molecule CCR5 antagonists are being developed to treat HIV-1 infection. It has been reported that such CCR5 antagonists, including TAK-779, bind to a putative binding pocket formed by transmembrane domains (TMs) 1, 2, 3 and 7 of CCR5, indicating the importance of the conformational changes of the TMs during virus entry. In this report, using a single-round infection assay with human CCR5 and its substitution mutants, we demonstrated that a new CCR5 antagonist, TAK-220, shares the putative interacting amino acid residues Asn252 and Leu255 in TM6 with TAK-779 but also requires the distinct residues Gly163 and Ile198 in TMs 4 and 5, respectively, for its inhibitory effect. We suggested that, together with molecular models of the interactions between the drugs and CCR5, the inhibitory activity of TAK-220 could involve direct interactions with amino acid residues in TMs 4, 5, and 6 in addition to those in the previously postulated binding pocket. The possible interaction of drugs with additional regions of the CCR5 molecule would help to develop a new small-molecule CCR5 antagonist.

SUBMITTER: Nishikawa M 

PROVIDER: S-EPMC1280122 | biostudies-literature | 2005 Nov

REPOSITORIES: biostudies-literature

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Analysis of binding sites for the new small-molecule CCR5 antagonist TAK-220 on human CCR5.

Nishikawa Masao M   Takashima Katsunori K   Nishi Toshiya T   Furuta Rika A RA   Kanzaki Naoyuki N   Yamamoto Yoshio Y   Fujisawa Jun-Ichi J  

Antimicrobial agents and chemotherapy 20051101 11


G protein-coupled receptor CCR5 is the main coreceptor for macrophage-tropic human immunodeficiency virus type 1 (HIV-1), and various small-molecule CCR5 antagonists are being developed to treat HIV-1 infection. It has been reported that such CCR5 antagonists, including TAK-779, bind to a putative binding pocket formed by transmembrane domains (TMs) 1, 2, 3 and 7 of CCR5, indicating the importance of the conformational changes of the TMs during virus entry. In this report, using a single-round i  ...[more]

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