An intracellular allosteric site for a specific class of antagonists of the CC chemokine G protein-coupled receptors CCR4 and CCR5.
A novel mechanism for antagonism of the human chemokine receptors CCR4 and CCR5 has been discovered with a series of small-molecule compounds that seems to interact with an allosteric, intracellular site on the receptor. The existence of this site is supported by a series of observations: 1) intracellular access of these antagonists is required for their activity; 2) specific, saturable binding of a radiolabeled antagonist requires the presence of CCR4; and 3) through engineering receptor chimeras by reciprocal transfer of C-terminal domains between CCR4 and CCR5, compound binding and the selective structure-activity relationships for antagonism of these receptors seem to be associated with the integrity of that intracellular region. Published antagonists from other chemical series do not seem to bind to the novel site, and their interaction with either CCR4 or CCR5 is not affected by alteration of the C-terminal domain. The precise location of the proposed binding site remains to be determined, but the known close association of the C-terminal domain, including helix 8, as a proposed intracellular region that interacts with transduction proteins (e.g., G proteins and beta-arrestin) suggests that this could be a generic allosteric site for chemokine receptors and perhaps more broadly for class A G protein-coupled receptors. The existence of such a site that can be targeted for drug discovery has implications for screening assays for receptor antagonists, which would need, therefore, to consider compound properties for access to this intracellular site.
Department of Discovery BioScience, AstraZeneca Research and Development Charnwood, Bakewell Rd., Loughborough, Leicestershire LE11 5RH, UK.
Glen
G
Andrews
Carolyn
C
Jones
Keith A
KA
Wreggett
D000495:Allosteric Site; D000595:Amino Acid Sequence; D000818:Animals; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D020013:Calcium Signaling; D002460:Cell Line; D054422:Chemokine CCL22 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D019742:Chemokines, CC / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003627:Data Interpretation, Statistical; D006801:Humans; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000166:cytology; D008969:Molecular Sequence Data; D015394:Molecular Structure; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019713:Receptors, CCR5 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D014162:Transfection
D065100:CCR5 Receptor Antagonists; D054422:Chemokine CCL22; D018946:Chemokine CCL5; D019742:Chemokines, CC; D054398:Receptors, CCR4; D019713:Receptors, CCR5; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins