Human Interferon-Inducible 10-kDa Protein and Human Interferon-Inducible T Cell α Chemoattractant Are Allotopic Ligands for Human CXCR3: Differential Binding to Receptor States

Cox, Mary Ann; Jenh, Chung‐Her; Gonsiorek, Waldemar; Fine, Jay S.; Narula, Satwant K.; Zavodny, Paul J.; Hipkin, R. William

doi:10.1124/mol.59.4.707

Cited by 115 publications

(98 citation statements)

References 20 publications

(16 reference statements)

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“…In contrast, CXCL11 fully displaced 125 I-CXCL10 from CXCR3WT. Similar findings have been reported by Cox et al, suggestive of allotopic binding of CXCL10 and CXCL11 to at least two different conformations of CXCR3 [22]. CXCL9 was a poor competitor of labeled CXCL10 and CXCL11, suggesting that it binds to either a distinct site or conformation of CXCR3.…”

Section: Discussionsupporting

confidence: 88%

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Molecular characterization of the chemokine receptor CXCR3: evidence for the involvement of distinct extracellular domains in a multi‐step model of ligand binding and receptor activation

2003

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CXCR3 is a chemokine receptor predominantly expressed on T lymphocytes, and binds the chemokines CXCL9 (Mig), CXCL10 (IP-10) and CXCL11 (I-TAC). Here, we have investigated the role of the extracellular domains of CXCR3 in ligand selectivity and receptor activation by assessing the ligand binding and chemotactic responses of chimeric CXCR3/CXCR1 constructs. Our data reveal that the second extracellular loop of CXCR3 is essential for receptor activation in response to all CXCR3 ligands. In contrast, the N terminus and first extracellular loop of CXCR3 play some role in CXCL10-and CXCL11-mediated activation but are dispensable for CXCL9-induced signaling. The third extracellular loop of CXCR3 is important only for CXCL9-and CXCL10-induced chemotaxis. Binding studies suggest that the CXCR3 ligands bind to distinct sites composed of multiple domains of CXCR3 and that high-affinity binding and receptor activation are disparate functions. Collectively, our data support a multi-site model for CXCR3 interactions with its agonists, in which several extracellular domains of CXCR3 contribute to ligand binding and the induction of receptor activation. The development of antagonists targeting the second extracellular loop of CXCR3 should impede receptor activation and aid the treatment of several human inflammatory disorders.

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Section: Discussionsupporting

confidence: 88%

“…An interesting observation of our study is that whilst 125 I-CXCL11 bound to the Chi-6, Chi-7 and Chi8 constructs, we were unable to demonstrate detectable binding of 125 I-CXCL10 to the same constructs. A previous study has shown that whilst CXCL11 binds to both the R and R* conformations of CXCR3, CXCL10 can only bind to the R* state [22].…”

Section: Discussionmentioning

confidence: 92%

Molecular characterization of the chemokine receptor CXCR3: evidence for the involvement of distinct extracellular domains in a multi‐step model of ligand binding and receptor activation

2003

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“…A previous study of CXCR3 has shown that G protein coupling can markedly influence chemokine binding, with the ligand CXCL10 only able to bind to chemokine receptor CXCR3 that is precoupled to G protein [23]. In light of these data, the inability of the E274Q mutant to bind CXCL16 might be explained by an inability of the construct to couple to G proteins.…”

Section: E274 Is Critical For the Recognition Of Soluble But Not Membmentioning

confidence: 88%

Site‐directed mutagenesis of the chemokine receptor CXCR6 suggests a novel paradigm for interactions with the ligand CXCL16

2008

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Chemokine receptor CXCR6 mediates the chemotaxis and adhesion of leukocytes to soluble and membrane-anchored forms of CXCL16, and is an HIV-1 co-receptor. Here, we describe the effects of mutation of acidic extracellular CXCR6 residues on receptor function. Although most CXCR6 mutants examined were expressed at levels similar to wild-type (WT) CXCR6, an N-terminal E3Q mutant was poorly expressed, which may explain previously reported protective effects of a similar single nucleotide polymorphism, with respect to late-stage HIV-1 infection. In contrast to several other chemokine receptors, mutation of the CXCR6 N terminus and inhibition of post-translational modifications of this region were without effect on receptor function. Likewise, N-terminal extension of CXCL16 resulted in a protein with decent potency and efficacy in chemotaxis and not, as anticipated, a CXCR6 antagonist. D176N and E274Q CXCR6 mutants were unable to interact with soluble CXCL16, suggesting a critical role for D176 and E274 in ligand binding. Intriguingly, although unable to interact with soluble CXCL16, the E274Q mutant could promote robust adhesion to membrane-anchored CXCL16, suggesting that soluble and membrane-bound forms of CXCL16 possess distinct conformations. Collectively, our data suggest a novel paradigm for the CXCR6:CXCL16 interaction, a finding which may impact the discovery of small-molecule antagonists of CXCR6.

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“…Despite discrepancies in the literature concerning the rank order potency of the three CXCR3 ligands, all are considered to be specific agonists for this receptor (Cole et al, 1998;Wang et al, 2000;Cox et al, 2001;Xanthou et al, 2003). Presumably, they function redundantly in vivo to ensure proper immunomodulatory tone, as suggested by the viability of CXCL10-deficient mice ; however, Cox et al (2001) have asserted that CXCL10 and CXCL11 bind to different states of the receptor in an allotopic manner.…”

mentioning

confidence: 99%

“…Presumably, they function redundantly in vivo to ensure proper immunomodulatory tone, as suggested by the viability of CXCL10-deficient mice ; however, Cox et al (2001) have asserted that CXCL10 and CXCL11 bind to different states of the receptor in an allotopic manner. It is therefore important to investigate whether small molecule nonpeptide antagonists can interfere with receptor activation to either of these ligands.…”

mentioning

confidence: 99%

Pharmacological Characterization of CXC Chemokine Receptor 3 Ligands and a Small Molecule Antagonist

Heise¹,

Pahuja²,

Hudson³

et al. 2005

J Pharmacol Exp Ther

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The CXC chemokine receptor 3 (CXCR3) is predominantly expressed on T helper type 1 (Th1) cells that are involved in inflammatory diseases. The three CXCR3 ligands CXCL9, CXCL10, and CXCL11 are produced at sites of inflammation and elicit migration of pathological Th1 cells. Here, we are the first to characterize the pharmacological potencies and specificity of a CXCR3 antagonist, N-1R- [3-(4-ethoxy-phenyl of 7 to 18 nM). NBI-74330 was selective for CXCR3 because it showed no significant inhibition of chemotactic responses to other chemokines and did not inhibit radioligand binding to a panel of nonchemokine G-protein coupled receptors. There was a striking difference in potencies among the three CXCR3 ligands, with CXCL11 Ͼ Ͼ CXCL10 Ͼ CXCL9. A comparison of the rank order of K i values with the rank order of monocyte production levels of these three ligands revealed a precise inverse correlation, suggesting that the weaker receptor affinities of CXCL9 and CXCL10 were physiologically compensated for by an elevated expression, perhaps to maintain effectiveness of each ligand under physiological conditions.

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Human Interferon-Inducible 10-kDa Protein and Human Interferon-Inducible T Cell α Chemoattractant Are Allotopic Ligands for Human CXCR3: Differential Binding to Receptor States

Cited by 115 publications

References 20 publications

Molecular characterization of the chemokine receptor CXCR3: evidence for the involvement of distinct extracellular domains in a multi‐step model of ligand binding and receptor activation

Molecular characterization of the chemokine receptor CXCR3: evidence for the involvement of distinct extracellular domains in a multi‐step model of ligand binding and receptor activation

Site‐directed mutagenesis of the chemokine receptor CXCR6 suggests a novel paradigm for interactions with the ligand CXCL16

Pharmacological Characterization of CXC Chemokine Receptor 3 Ligands and a Small Molecule Antagonist

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