Structural basis of CXCR4 assembly and regulation
Summary: CXC chemokine receptor 4 (CXCR4) is a well-established drug target and a key representative of the chemokine receptor family. Chemokine receptors tend to assemble, and this assembly plays a critical role in regulating their functions. However, structural information regarding the organizati...
Saved in:
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-02-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725000269 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832573193947185152 |
|---|---|
| author | Aijun Liu Yezhou Liu Richard D. Ye |
| author_facet | Aijun Liu Yezhou Liu Richard D. Ye |
| author_sort | Aijun Liu |
| collection | DOAJ |
| description | Summary: CXC chemokine receptor 4 (CXCR4) is a well-established drug target and a key representative of the chemokine receptor family. Chemokine receptors tend to assemble, and this assembly plays a critical role in regulating their functions. However, structural information regarding the organization of these receptors remains limited. Here, we present the cryoelectron microscopy (cryo-EM) structure of a CXCR4 homo-tetramer. In this tetramer, each protomer interfaces with adjacent protomers via TM1/2 and TM5/6/7, aligning at a 90° angle to assemble into a C4 rotationally symmetric arrangement. Each protomer allosterically regulates the others, with Q272 in the ECL3 loop interacting with K38 (TM1) and V99 (TM2) of the adjacent protomer, resulting in a mutually inhibitory configuration. These findings reveal an allosteric and antagonistic mechanism that prevents excessive activation, providing a structural framework for understanding the molecular mechanisms driving CXCR4 self-assembly and offering insights that could inspire further therapeutic strategies. |
| format | Article |
| id | doaj-art-140d06b86cf8496fbfef43c0079db1df |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-140d06b86cf8496fbfef43c0079db1df2025-02-02T05:27:05ZengElsevierCell Reports2211-12472025-02-01442115255Structural basis of CXCR4 assembly and regulationAijun Liu0Yezhou Liu1Richard D. Ye2Dongguan Songshan Lake Central Hospital, Dongguan Third People’s Hospital, The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan, Guangdong 523326, China; Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China; Corresponding authorDongguan Songshan Lake Central Hospital, Dongguan Third People’s Hospital, The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan, Guangdong 523326, China; Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, ChinaDongguan Songshan Lake Central Hospital, Dongguan Third People’s Hospital, The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan, Guangdong 523326, China; 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 518000, China; Corresponding authorSummary: CXC chemokine receptor 4 (CXCR4) is a well-established drug target and a key representative of the chemokine receptor family. Chemokine receptors tend to assemble, and this assembly plays a critical role in regulating their functions. However, structural information regarding the organization of these receptors remains limited. Here, we present the cryoelectron microscopy (cryo-EM) structure of a CXCR4 homo-tetramer. In this tetramer, each protomer interfaces with adjacent protomers via TM1/2 and TM5/6/7, aligning at a 90° angle to assemble into a C4 rotationally symmetric arrangement. Each protomer allosterically regulates the others, with Q272 in the ECL3 loop interacting with K38 (TM1) and V99 (TM2) of the adjacent protomer, resulting in a mutually inhibitory configuration. These findings reveal an allosteric and antagonistic mechanism that prevents excessive activation, providing a structural framework for understanding the molecular mechanisms driving CXCR4 self-assembly and offering insights that could inspire further therapeutic strategies.http://www.sciencedirect.com/science/article/pii/S2211124725000269CP: Molecular biology |
| spellingShingle | Aijun Liu Yezhou Liu Richard D. Ye Structural basis of CXCR4 assembly and regulation Cell Reports CP: Molecular biology |
| title | Structural basis of CXCR4 assembly and regulation |
| title_full | Structural basis of CXCR4 assembly and regulation |
| title_fullStr | Structural basis of CXCR4 assembly and regulation |
| title_full_unstemmed | Structural basis of CXCR4 assembly and regulation |
| title_short | Structural basis of CXCR4 assembly and regulation |
| title_sort | structural basis of cxcr4 assembly and regulation |
| topic | CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725000269 |
| work_keys_str_mv | AT aijunliu structuralbasisofcxcr4assemblyandregulation AT yezhouliu structuralbasisofcxcr4assemblyandregulation AT richarddye structuralbasisofcxcr4assemblyandregulation |