Molecular basis for chemokine recognition and activation of XCR1

• 成果类型: Article
• 署名作者: Zhang, Xuan; Schlimgen, Roman R.; Singh, Stephanie; Tomani, Michael P.; Volkman, Brian F.; Zhang, Cheng
• 署名单位: Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Medical College of Wisconsin; Medical College of Wisconsin; University of Rochester
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11105
• DOI: 10.1073/pnas.2405732121
• 发表日期: 2024-11-26
• 关键词: gui membrane-builder; structural basis; dendritic cells; c-chemokine; human lymphotactin; software news; receptor; identification; purification; antagonism

摘要

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.