Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China.
Dongguan Songshan Lake Central Hospital, Dongguan Third People's Hospital, The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan, Guangdong 523326, China.
Proc Natl Acad Sci U S A. 2024 Oct 15;121(42):e2403217121. doi: 10.1073/pnas.2403217121. Epub 2024 Oct 8.
Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a viral G protein-coupled receptor, KSHV-GPCR, that contributes to KSHV immune evasion and pathogenesis of Kaposi's sarcoma. KSHV-GPCR shares a high similarity with CXC chemokine receptors CXCR2 and can be activated by selected chemokine ligands. Like other herpesvirus-encoded GPCRs, KSHV-GPCR is characterized by its constitutive activity by coupling to various G proteins. We investigated the structural basis of ligand-dependent and constitutive activation of KSHV-GPCR, obtaining high-resolution cryo-EM structures of KSHV-GPCR-Gi complexes with and without the bound CXCL1 chemokine. Analysis of the apo-KSHV-GPCR-Gi structure (2.81 Å) unraveled the involvement of extracellular loop 2 in constitutive activation of the receptor. In comparison, the CXCL1-bound KSHV-GPCR-Gi structure (3.01 Å) showed a two-site binding mode and provided detailed information of CXCL1 binding to a chemokine receptor. The dual activation mechanism employed by KSHV-GPCR represents an evolutionary adaptation for immune evasion and contributes to the pathogenesis of Kaposi's sarcoma. Together with results from functional assays that confirmed the structural models, these findings may help to develop therapeutic strategies for KSHV infection.
卡波西肉瘤相关疱疹病毒（KSHV）编码一种病毒 G 蛋白偶联受体，即 KSHV-GPCR，它有助于 KSHV 免疫逃逸和卡波西肉瘤的发病机制。KSHV-GPCR 与 CXC 趋化因子受体 CXCR2 具有高度相似性，可被选定的趋化因子配体激活。与其他疱疹病毒编码的 GPCR 一样，KSHV-GPCR 通过与各种 G 蛋白偶联而具有组成型活性的特征。我们研究了 KSHV-GPCR 的配体依赖性和组成型激活的结构基础，获得了与结合的 CXCL1 趋化因子结合和不结合的 KSHV-GPCR-Gi 复合物的高分辨率冷冻电镜结构。对 apo-KSHV-GPCR-Gi 结构（2.81 Å）的分析揭示了细胞外环 2 参与受体的组成型激活。相比之下，结合 CXCL1 的 KSHV-GPCR-Gi 结构（3.01 Å）显示了双结合模式，并提供了 CXCL1 与趋化因子受体结合的详细信息。KSHV-GPCR 采用的双重激活机制代表了对免疫逃逸的进化适应，有助于卡波西肉瘤的发病机制。与证实结构模型的功能测定结果一起，这些发现可能有助于开发针对 KSHV 感染的治疗策略。
