Research ArticleChemokine Signaling

Structural basis for chemokine recognition by a G protein–coupled receptor and implications for receptor activation

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Sci. Signal.  21 Mar 2017:
Vol. 10, Issue 471, eaah5756
DOI: 10.1126/scisignal.aah5756

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How receptors view monomers versus dimers

Chemokines are proteins that stimulate cell migration in processes such as development, immune responses, and metastasis. Monomeric, dimeric, and oligomeric forms of chemokines can engage their cognate G protein–coupled receptors. Both the G protein–dependent and β-arrestin–dependent signaling pathways downstream of chemokine receptors must be activated to induce cell migration. Previous studies showed that a locked dimeric form of CXCL12 (LD CXCL12) fails to activate β-arrestin–dependent signaling after binding to its receptor CXCR4. Ziarek et al. solved the NMR structure of CXCR4 bound to a locked monomeric form of CXCL12 (LM CXCL12). LM CXCL12 physically interacted with the receptor differently than did the dimeric chemokine, and it stimulated both CXCR4-dependent signaling pathways to induce migration. Analysis of a hybrid NMR- and x-ray–based structure provided insights into the conformational changes required for chemokine receptor signaling, which may aid in designing drugs to target the chemokine family.