Cryo-EM structure of monomeric CXCL12-bound CXCR4 in the active state
Yezhou Liu,
Aijun Liu,
Xinyu Li,
Qiwen Liao,
Weijia Zhang,
Lizhe Zhu,
Richard D. Ye
Affiliations
Yezhou Liu
Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China
Aijun Liu
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
Xinyu Li
Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China
Qiwen Liao
Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China
Weijia Zhang
Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China
Lizhe Zhu
Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China; Corresponding author
Richard D. Ye
Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong 518048, China; Corresponding author
Summary: CXCR4 binding of its endogenous agonist CXCL12 leads to diverse functions, including bone marrow retention of hematopoietic progenitors and cancer metastasis. However, the structure of the CXCL12-bound CXCR4 remains unresolved despite available structures of CXCR4 in complex with antagonists. Here, we present the cryoelectron microscopy (cryo-EM) structure of the CXCL12-CXCR4-Gi complex at an overall resolution of 2.65 Å. CXCL12 forms a 1:1 stoichiometry complex with CXCR4, following the two-site model. The first 8 amino acids of mature CXCL12 are crucial for CXCR4 activation by forming polar interactions with minor sub-pocket residues in the transmembrane binding pocket. The 3.2-Å distance between V3 of CXCL12 and the “toggle switch” W6.48 marks the deepest insertion among all chemokine-receptor pairs, leading to conformational changes of CXCR4 for G protein activation. These results, combined with functional assays and computational analysis, provide the structural basis for CXCR4 activation by CXCL12.
