The binding mechanism of an anti-multiple myeloma antibody to the human GPRC5D homodimer

doi:10.1038/s41467-024-49625-y

KMS > iHuman研究所

	The binding mechanism of an anti-multiple myeloma antibody to the human GPRC5D homodimer
	Yan, Pengfei1,2 ; Lin, Xi1 ; Wu, Lijie1 ; Xu, Lu1,3 ; Li, Fei1 ; Liu, Junlin1 ; Xu, Fei1,2,4
	2024-06-19
发表期刊	NATURE COMMUNICATIONS (IF:14.7[JCR-2023],16.1[5-Year])
EISSN	2041-1723
卷号	15 期号:1
发表状态	已发表
DOI	10.1038/s41467-024-49625-y
摘要	GPRC5D is an atypical Class C orphan G protein-coupled receptor. Its high expression on the surface of multiple myeloma cells has rendered it an attractive target for therapeutic interventions, including monoclonal antibodies, CAR-T cells, and T-cell engagers. Despite its therapeutic potential, the insufficient understanding regarding of the receptor's structure and antibody recognition mechanism has impeded the progress of effective therapeutic development. Here, we present the structure of GPRC5D in complex with a preclinical-stage single-chain antibody (scFv). Our structural analysis reveals that the GPRC5D presents a close resemblance to the typical Class C GPCRs in the transmembrane region. We identify a distinct head-to-head homodimer arrangement and interface mainly involving TM4, setting it apart from other Class C homo- or hetero-dimers. Furthermore, we elucidate the binding site engaging a sizable extracellular domain on GPRC5D for scFv recognition. These insights not only unveil the distinctive dimer organization of this unconventional Class C GPCR but also hold the potential to advance drug development targeting GPRC5D for the treatment of multiple myeloma.
URL	查看原文
收录类别	SCI
语种	英语
资助项目	National Natural Science Foundation of China (National Science Foundation of China)[32071194] ; National Natural Science Foundation of China[JYJC202233] ; Chenguang Program of Shanghai Education Development Foundation[23CGA79]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:001252637700012
出版者	NATURE PORTFOLIO
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/408310
专题	iHuman研究所生命科学与技术学院 iHuman研究所_公共科研平台_IT平台 iHuman研究所_公共科研平台_昆虫细胞培养平台 iHuman研究所_PI研究组_徐菲组 iHuman研究所_科学装置(X)_膜蛋白同步辐射线站生命科学与技术学院_博士生
通讯作者	Xu, Fei
作者单位	1.ShanghaiTech Univ, iHuman Inst, Shanghai, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai Key Lab High resolut Electron Microscopy, Shanghai, Peoples R China 3.JiKang Therapeut, Shanghai, Peoples R China 4.Shanghai Clin Res & Trial Ctr, Shanghai, Peoples R China
第一作者单位	iHuman研究所; 生命科学与技术学院
通讯作者单位	iHuman研究所; 生命科学与技术学院
第一作者的第一单位	iHuman研究所
推荐引用方式 GB/T 7714	Yan, Pengfei,Lin, Xi,Wu, Lijie,et al. The binding mechanism of an anti-multiple myeloma antibody to the human GPRC5D homodimer[J]. NATURE COMMUNICATIONS,2024,15(1).
APA	Yan, Pengfei.,Lin, Xi.,Wu, Lijie.,Xu, Lu.,Li, Fei.,...&Xu, Fei.(2024).The binding mechanism of an anti-multiple myeloma antibody to the human GPRC5D homodimer.NATURE COMMUNICATIONS,15(1).
MLA	Yan, Pengfei,et al."The binding mechanism of an anti-multiple myeloma antibody to the human GPRC5D homodimer".NATURE COMMUNICATIONS 15.1(2024).