Abstract
CC-chemokine receptor 5 (CCR5) is a specific co-receptor allowing the entry of human immunodeficiency virus type 1 (HIV-1). The LC4 region in CCR5 is required for HIV-1 entry into the cells. In this study, the solution structure of LC4 in SDS micelles was elucidated by using standard 1H two-dimensional NMR spectroscopy, circular dichroism, and fluorescdence quenching. The LC4 structure adopts two helical structures, whereas the C-terminal part remains unstructured. The positions in which LC4 binds to the HIV-1 inhibitory peptide LC5 were determined by docking calculations in addition to NMR data. The poses showed the importance of the hydrophobic interface of the assembled structures. The solution structure of LC4 elucidated in the present work provides a structural basis for further studies on the HIV-1 inhibitory function of the LC4 region.
Highlights
CC-chemokine receptor 5 (CCR5) is a member of the Gprotein-coupled receptor superfamily and is comprised of seven transmembrane segments [1]
The solution structure of LC4 in sodium dodecyl sulfate (SDS) micelles presented here provides an insight into its functional interaction with CCR5 at an atomic level
The Circular dichroism (CD) spectra showed that LC4 assumes a random-coil conformation in an aqueous environment, but a helical conformation in SDS micelles
Summary
CC-chemokine receptor 5 (CCR5) is a member of the Gprotein-coupled receptor superfamily and is comprised of seven transmembrane segments [1]. To gain entry into cells, HIV-1 requires a CD4 receptor and co-receptors such as CCR5 and CXCR4 [5,6]. Blocking HIV-1 entry into the cell naturally leads to the inhibition of its infection and replication [7]. A novel synthetic LC5 peptide (222LRCRNEKKRHRAVRLIFTI240) that inhibits HIV-1 infection of MT-4 cells was reported [8]. It is suggested that the LC5 peptide interacts with the LC4 region (157VFASLPGIIFTRSQKEGL174) corresponding to the fourth transmembrane segment of CCR5 [8]. The peptide possesses an a-helical structure in the C-terminal region, and there is a hydrophobic cluster on the surface of the peptide. Knowledge of the solution conformation of LC4 in the membrane is crucial for understanding the functional mechanism of the LC4 region
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