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De novo Design of A Fusion Protein Tool for GPCR Research
Open accessPreprint — published as 10.1073/pnas.2422360122
Abstract
G protein-coupled receptors (GPCRs) play pivotal roles in cellular signaling and represent prominent drug targets. Structural elucidation of GPCRs is crucial for drug discovery efforts. However, structural studies of GPCRs remain challenging, particularly for inactive state structures, which often require extensive protein engineering. Here, we present a de novo design strategy termed “click fusion” for generating fusion proteins to facilitate GPCR structural studies. Our method involves the rational design of structurally stable protein domains rigidly linked to GPCRs. The resulting fusion protein enhances the thermostability of the target GPCR and aids in determining GPCR structures via cryo-electron microscopy (cryo-EM). We further demonstrate that the designed fusion protein can be transferred among structurally similar GPCRs with minor adjustments to the linker region. Our study introduces a promising approach for facilitating GPCR structural studies and advancing drug discovery efforts.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
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Metadata
- Authors
- Gao, K., Zhang, X., Nie, J., Meng, H., Zhang, W., Tian, B., & Liu, X.
- Affiliations
- Center for Life Sciences (CN)
- Xiangya Hospital Central South University (CN)
- Corresponding author
- Gao, Kaixuan
- Zhang, Xin
- Nie, Jia
- Zhang, Weishe
- Liu, Xiangyu
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- openRxiv
- Published
- 2024-09-15
- Volume
- 122
- Issue
- 29
- Pages
- e2422360122-e2422360122
- ISSN
- 0027-8424 (ISSN-L)
- PMC
- PMC12304938
- OpenAlex
- W4412399856
- Cited by
- 8
- References
- 1
- Citations by year
- 2026: 6 · 2025: 2
- FWCI
- 2.40
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- www.biorxiv.org/about/FAQ#license (vor)
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- Funders
- National Natural Science Foundation of China (Grant 81974236)
- Young Scientists Fund (Grant 32122041)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Keywords
- G protein-coupled receptors, de novo protein design, fusion protein, protein thermal stability, linker engineering, drug discovery
- MeSH terms
- Humans, Models, Molecular, Protein Conformation, Recombinant Fusion Proteins, Protein Engineering, Cryoelectron Microscopy, Receptors, G-Protein-Coupled
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