A homotrimeric GPCR architecture of the human cytomegalovirus revealed by cryo-EM

doi:10.1038/s41421-024-00684-x

. 2024 May 16;10(1):52.

doi: 10.1038/s41421-024-00684-x.

A homotrimeric GPCR architecture of the human cytomegalovirus revealed by cryo-EM

Yanyan Chen^#¹, Yang Li^#², Qingtong Zhou^#^{1

3}, Zhaotong Cong³, Shi Lin¹, Jiahui Yan⁴, Xianyue Chen¹, Dehua Yang^{5

6}, Tianlei Ying⁷, Ming-Wei Wang^{8

9

10

11}

Affiliations

¹ Research Center for Deepsea Bioresources, Sanya, Hainan, China.
² Shanghai Institute of Infectious Disease and Biosecurity, Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
³ Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
⁴ The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁵ Research Center for Deepsea Bioresources, Sanya, Hainan, China. dhyang@simm.ac.cn.
⁶ The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. dhyang@simm.ac.cn.
⁷ Shanghai Institute of Infectious Disease and Biosecurity, Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China. tlying@fudan.edu.cn.
⁸ Research Center for Deepsea Bioresources, Sanya, Hainan, China. mwwang@simm.ac.cn.
⁹ Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China. mwwang@simm.ac.cn.
¹⁰ Department of Chemistry, School of Science, The University of Tokyo, Tokyo, Japan. mwwang@simm.ac.cn.
¹¹ School of Pharmacy, Hainan Medical University, Haikou, Hainan, China. mwwang@simm.ac.cn.

^# Contributed equally.

PMID: 38750025
PMCID: PMC11096299
DOI: 10.1038/s41421-024-00684-x

A homotrimeric GPCR architecture of the human cytomegalovirus revealed by cryo-EM

Yanyan Chen et al. Cell Discov. 2024.

. 2024 May 16;10(1):52.

doi: 10.1038/s41421-024-00684-x.

Authors

Yanyan Chen^#¹, Yang Li^#², Qingtong Zhou^#^{1

3}, Zhaotong Cong³, Shi Lin¹, Jiahui Yan⁴, Xianyue Chen¹, Dehua Yang^{5

6}, Tianlei Ying⁷, Ming-Wei Wang^{8

9

10

11}

Affiliations

¹ Research Center for Deepsea Bioresources, Sanya, Hainan, China.
² Shanghai Institute of Infectious Disease and Biosecurity, Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
³ Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
⁴ The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁵ Research Center for Deepsea Bioresources, Sanya, Hainan, China. dhyang@simm.ac.cn.
⁶ The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. dhyang@simm.ac.cn.
⁷ Shanghai Institute of Infectious Disease and Biosecurity, Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China. tlying@fudan.edu.cn.
⁸ Research Center for Deepsea Bioresources, Sanya, Hainan, China. mwwang@simm.ac.cn.
⁹ Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China. mwwang@simm.ac.cn.
¹⁰ Department of Chemistry, School of Science, The University of Tokyo, Tokyo, Japan. mwwang@simm.ac.cn.
¹¹ School of Pharmacy, Hainan Medical University, Haikou, Hainan, China. mwwang@simm.ac.cn.

^# Contributed equally.

PMID: 38750025
PMCID: PMC11096299
DOI: 10.1038/s41421-024-00684-x

No abstract available

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Cryo-EM structure of homotrimeric UL78.**
a Representative cryo-EM 2D classification averages of UL78 homotrimers. b Cryo-EM density map and cartoon representation of UL78 homotrimer. The sharpened cryo-EM density map at the 0.23 threshold shown as a light gray surface indicates a micelle diameter of 10 nm. c Extracellular and intracellular views of TMs show the interfaces of UL78 trimer. d Structural comparison with the inactive-state CXCR3 structure (PDB: 8K2W) shows conformational changes of TMs 5–7 and ICL2 of UL78. e Steric clashes between the G_i α5 helix (extracted from the aligned CXCL10-bound CXCR3−G_i, PDB: 8K2X) and the intracellular faces of inactive CXCR3 (PDB: 8K2W) and UL78. f Magnified view of ICL2 within the intracellular pocket and its interactions with TMs and ICL1. g Magnified view of ECL2 within the extracellular pocket and its interactions with TMs. h Detection of UL78 trimer formation by BiFC-BRET assay. Data are means ± SEM from at least three independent experiments. All data were analyzed by one-way ANOVA and Dunnett’s test, ***P < 0.001. Additional mutations around the ECL2 (C109^TM3A, W184^ECL2A, Q188^ECL2A and R254^TM6A) consistently decreased the trimer formation by 52%, 60%, 56% and 49%, respectively. i Homotrimer interface of UL78, where two protomers are displayed in surface representation, and one in cartoon. Magnified views of the tightly packed TM5 from three protomers (left) and the intracellular bottom of the trimer interface (right) are shown. j Interface interactions among three UL78 protomers. The colors of the circles and lines are proportional to the residue positions and the interaction types, respectively. k Scatter plot of the TMD interface in GPCRs. The y axis represents the TMD interface area per protomer, and the x axis is the number of residues from individual protomers in the TMD interface. The former is calculated using freeSASA, while the latter is counted once the residual interface area is over 1 Å². PDBs with multiple protomers are averaged in the plot. The circles are colored according to GPCR subfamilies and their diameters are proportional to the number of TMs in the interface. l Representative TM packings in GPCR dimer structures. The TMs in the interface are colored in orange and blue, respectively. Only the TMDs are shown for clarity.

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References

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[1] Vischer HF, et al. Trends Pharm. Sci. 2006;27:56–63. doi: 10.1016/j.tips.2005.11.006. - DOI - PubMed

[2] Vischer HF, et al. Trends Pharm. Sci. 2006;27:56–63. doi: 10.1016/j.tips.2005.11.006. - DOI - PubMed

[3] Rosenkilde, M. M. et al. Annu. Rev. Virol.9, 329–351 (2022). - PMC - PubMed

[4] Rosenkilde, M. M. et al. Annu. Rev. Virol.9, 329–351 (2022). - PMC - PubMed

[5] Vischer HF, et al. Nat. Rev. Drug Discov. 2014;13:123–139. doi: 10.1038/nrd4189. - DOI - PubMed

[6] Vischer HF, et al. Nat. Rev. Drug Discov. 2014;13:123–139. doi: 10.1038/nrd4189. - DOI - PubMed

[7] Burg JS, et al. Science. 2015;347:1113–1117. doi: 10.1126/science.aaa5026. - DOI - PMC - PubMed

[8] Burg JS, et al. Science. 2015;347:1113–1117. doi: 10.1126/science.aaa5026. - DOI - PMC - PubMed

[9] Tsutsumi N, et al. Sci. Adv. 2022;8:eabl5442. doi: 10.1126/sciadv.abl5442. - DOI - PMC - PubMed

[10] Tsutsumi N, et al. Sci. Adv. 2022;8:eabl5442. doi: 10.1126/sciadv.abl5442. - DOI - PMC - PubMed

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A homotrimeric GPCR architecture of the human cytomegalovirus revealed by cryo-EM

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A homotrimeric GPCR architecture of the human cytomegalovirus revealed by cryo-EM

Authors

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Conflict of interest statement

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