Identification of a Putative Intracellular Allosteric Antagonist Binding-Site in the CXC Chemokine Receptors 1 and 2
The chemokine receptors CXCR1 and CXCR2 are G-protein-coupled receptors (GPCRs) implicated in mediating cellular functions associated with the inflammatory response. Potent CXCR2 receptor antagonists have been discovered, some of which have recently entered clinical development. The aim of this stud...
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Veröffentlicht in: | Molecular pharmacology 2008-11, Vol.74 (5), p.1193-1202 |
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Sprache: | eng |
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Zusammenfassung: | The chemokine receptors CXCR1 and CXCR2 are G-protein-coupled receptors (GPCRs) implicated in mediating cellular functions
associated with the inflammatory response. Potent CXCR2 receptor antagonists have been discovered, some of which have recently
entered clinical development. The aim of this study was to identify key amino acid residue differences between CXCR1 and CXCR2
that influence the relative antagonism by two compounds that have markedly different chemical structures. By investigating
the effects of domain switching and point mutations, we found that the second extracellular loop, which contained significant
amino acid sequence diversity, was not important for compound antagonism. We were surprised to find that switching the intracellular
C-terminal 60 amino acid domains of CXCR1 and CXCR2 caused an apparent reversal of antagonism at these two receptors. Further
investigation showed that a single amino acid residue, lysine 320 in CXCR2 and asparagine 311 in CXCR1, plays a predominant
role in describing the relative antagonism of the two compounds. Homology modeling studies based on the structure of bovine
rhodopsin indicated a potential intracellular antagonist binding pocket involving lysine 320. We conclude that residue 320
in CXCR2 forms part of a potential allosteric binding pocket on the intracellular side of the receptor, a site that is distal
to the orthosteric site commonly assumed to be the location of antagonist binding to GPCRs. The existence of a common intracellular
allosteric binding site at GPCRs related to CXCR2 may be of value in the design of novel antagonists for therapeutic intervention. |
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ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.107.044610 |