Molecular basis for chemokine recognition and activation of XCR1. Proc Natl Acad Sci U S A 2024 Nov 26;121(48):e2405732121
Date
11/20/2024Pubmed ID
39565315Pubmed Central ID
PMC11621518DOI
10.1073/pnas.2405732121Scopus ID
2-s2.0-85210106138 (requires institutional sign-in at Scopus site) 12 CitationsAbstract
The X-C motif chemokine receptor XCR1, which selectively binds to the chemokine XCL1, is highly expressed in conventional dendritic cells subtype 1 (cDC1s) and crucial for their activation. Modulating XCR1 signaling in cDC1s could offer novel opportunities in cancer immunotherapy and vaccine development by enhancing the antigen presentation function of cDC1s. To investigate the molecular mechanism of XCL-induced XCR1 signaling, we determined a high-resolution structure of the human XCR1 and Gi complex with an engineered form of XCL1, XCL1 CC3, by cryoelectron microscopy. Through mutagenesis and structural analysis, we elucidated the molecular details for the binding of the N-terminal segment of XCL1 CC3, which is vital for activating XCR1. The unique arrangement within the XCL1 CC3 binding site confers specificity for XCL1 in XCR1. We propose an activation mechanism for XCR1 involving structural alterations of key residues at the bottom of the XCL1 binding pocket. These detailed insights into XCL1 CC3-XCR1 interaction and XCR1 activation pave the way for developing novel XCR1-targeted therapeutics.
Author List
Zhang X, Schlimgen RR, Singh S, Tomani MP, Volkman BF, Zhang CAuthor
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Binding SitesChemokines, C
Cryoelectron Microscopy
Dendritic Cells
Humans
Models, Molecular
Protein Binding
Receptors, Chemokine
Receptors, G-Protein-Coupled
Signal Transduction
