Research ArticleCHEMOKINE RECEPTORS

Functional anatomy of the full-length CXCR4-CXCL12 complex systematically dissected by quantitative model-guided mutagenesis

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Science Signaling  14 Jul 2020:
Vol. 13, Issue 640, eaay5024
DOI: 10.1126/scisignal.aay5024

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Illuminating CXCR4 activation

The small secreted protein CXCL12 and its cognate GPCR CXCR4 mediate cell migration and are implicated in immune cell trafficking, HIV-1 infection, and metastasis. Thus, structural analysis of the CXCR4-CXCL12 complex has implications for designing therapeutics. Stephens et al. tested their previous structural model of CXCR4-CXCL12 with a large panel of mutations and charged residue swapping experiments in cell-based functional assays and identified critical interactions across the large interface of the complex that are important for CXCR4 activation. These results challenge the established “two-site” hypothesis of chemokine receptor activation and provide structural insights into the mechanism of CXCR4 signaling.

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