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 Arnold, Edward Arnold, Hiroaki Mitsuya

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)12688-12698
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number18
DOIs
StatePublished - May 5 2006

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CCR5 Receptors
Molecular interactions
Viruses
HIV-1
CC Chemokines
Binding Sites
Mutation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Maeda, K., Das, D., Ogata-Aoki, H., Nakata, H., Miyakawa, T., Tojo, Y., ... Mitsuya, H. (2006). Structural and molecular interactions of CCR5 inhibitors with CCR5. Journal of Biological Chemistry, 281(18), 12688-12698. https://doi.org/10.1074/jbc.M512688200
Maeda, Kenji ; Das, Debananda ; Ogata-Aoki, Hiromi ; Nakata, Hirotomo ; Miyakawa, Toshikazu ; Tojo, Yasushi ; Norman, Rachael ; Takaoka, Yoshikazu ; Ding, Jianping ; Arnold, Gail ; Arnold, Edward ; Mitsuya, Hiroaki. / Structural and molecular interactions of CCR5 inhibitors with CCR5. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 18. pp. 12688-12698.
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Maeda, K, Das, D, Ogata-Aoki, H, Nakata, H, Miyakawa, T, Tojo, Y, Norman, R, Takaoka, Y, Ding, J, Arnold, G, Arnold, E & Mitsuya, H 2006, 'Structural and molecular interactions of CCR5 inhibitors with CCR5', Journal of Biological Chemistry, vol. 281, no. 18, pp. 12688-12698. https://doi.org/10.1074/jbc.M512688200

Structural and molecular interactions of CCR5 inhibitors with CCR5. / Maeda, Kenji; Das, Debananda; Ogata-Aoki, Hiromi; Nakata, Hirotomo; Miyakawa, Toshikazu; Tojo, Yasushi; Norman, Rachael; Takaoka, Yoshikazu; Ding, Jianping; Arnold, Gail; Arnold, Edward; Mitsuya, Hiroaki.

In: Journal of Biological Chemistry, Vol. 281, No. 18, 05.05.2006, p. 12688-12698.

Research output: Contribution to journalArticle

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Maeda K, Das D, Ogata-Aoki H, Nakata H, Miyakawa T, Tojo Y et al. Structural and molecular interactions of CCR5 inhibitors with CCR5. Journal of Biological Chemistry. 2006 May 5;281(18):12688-12698. https://doi.org/10.1074/jbc.M512688200