Structure of bovine viral diarrhea virus E2 glycoprotein in complex with CD46 reveals the molecular basis of virus–receptor recognition
5 affiliations
- 1Department of Emergency Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
- 2Department of Hematology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
- 3Department of Veterinary Public Health, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, Jilin, China
- 4Laboratory of Emergency Medicine, Disaster Medicine Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
- 5Center for Design and Biomanufacturing of Anti-infective Agents, Institute for Advanced Study, Chengdu University, Chengdu 610106, Sichuan, China
Abstract
Bovine viral diarrhea virus (BVDV) is a major contagious pathogen of ruminants and imposes substantial economic burdens on the global livestock industry. The viral envelope glycoprotein E2 mediates host cell attachment by recognizing the CD46 receptor; however, the molecular basis of this interaction remains unclear. Here, we report the crystal structure of BVDV-1 E2 in complex with bovine CD46 at 3.1-Å resolution. The structure reveals that the SCR1-2 domains of CD46 engage the DII-DIV domains of E2 in a roughly antiparallel orientation. Atomic interactions at the E2/CD46 interface are dominated by van der Waals contacts, accompanied by only a limited number of hydrogen bonds, which explains the observed low-affinity binding between the two molecules. Structural analysis and mutagenesis studies identify key receptor features that govern host susceptibility to the virus and propose an interesting bipartite model: The D′/D interloop within SCR1 of CD46 likely serves as the “molecular determinant,” and key interface residues within SCR2 function as the “affinity regulator.” We further engineered CD46 decoy proteins exhibiting over 1,800-fold higher apparent binding to E2 than the wild-type receptor and demonstrated their potent virus-neutralizing activity. Collectively, these findings elucidate the molecular basis of CD46 recognition by BVDV, provide a structural framework for understanding the viral host range, and establish a receptor-based strategy for potential antiviral intervention.
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BibTeX
@article{duan2026structure,
title = {{Structure of bovine viral diarrhea virus E2 glycoprotein in complex with CD46 reveals the molecular basis of virus–receptor recognition}},
author = {Yanping Duan and Sheng Lin and Fei Wang and Yu You and Zimin Chen and Liyan Guo and Wenjie Gong and Lianjing Liang and Shiyuan Tang and Hai-fang Yu and Yarong He and Bin He and Zhi Wan and Yu Cao and Fanli Yang and Guangwen Lu},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2620643123},
url = {https://doi.org/10.1073/pnas.2620643123},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Structure of bovine viral diarrhea virus E2 glycoprotein in complex with CD46 reveals the molecular basis of virus–receptor recognition
AU - Yanping Duan
AU - Sheng Lin
AU - Fei Wang
AU - Yu You
AU - Zimin Chen
AU - Liyan Guo
AU - Wenjie Gong
AU - Lianjing Liang
AU - Shiyuan Tang
AU - Hai-fang Yu
AU - Yarong He
AU - Bin He
AU - Zhi Wan
AU - Yu Cao
AU - Fanli Yang
AU - Guangwen Lu
PY - 2026
DA - 2026/10/20
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2620643123
UR - https://doi.org/10.1073/pnas.2620643123
AB - Bovine viral diarrhea virus (BVDV) is a major contagious pathogen of ruminants and imposes substantial economic burdens on the global livestock industry. The viral envelope glycoprotein E2 mediates host cell attachment by recognizing the CD46 receptor; however, the molecular basis of this interaction remains unclear. Here, we report the crystal structure of BVDV-1 E2 in complex with bovine CD46 at 3.1-Å resolution. The structure reveals that the SCR1-2 domains of CD46 engage the DII-DIV domains of E2 in a roughly antiparallel orientation. Atomic interactions at the E2/CD46 interface are dominated by van der Waals contacts, accompanied by only a limited number of hydrogen bonds, which explains the observed low-affinity binding between the two molecules. Structural analysis and mutagenesis studies identify key receptor features that govern host susceptibility to the virus and propose an interesting bipartite model: The D′/D interloop within SCR1 of CD46 likely serves as the “molecular determinant,” and key interface residues within SCR2 function as the “affinity regulator.” We further engineered CD46 decoy proteins exhibiting over 1,800-fold higher apparent binding to E2 than the wild-type receptor and demonstrated their potent virus-neutralizing activity. Collectively, these findings elucidate the molecular basis of CD46 recognition by BVDV, provide a structural framework for understanding the viral host range, and establish a receptor-based strategy for potential antiviral intervention.
SN - 0027-8424
SN - 1091-6490
ER -