Volume 34, No 12, Dec 2024

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 34 Issue 12, December 2024: 846-858   |  Open Access

ORIGINAL ARTICLES

Accurate de novo design of heterochiral protein–protein interactions

Ke Sun^1,2,3,4,† , Sicong Li^2,3,4,† , Bowen Zheng^2,3,4,† , Yanlei Zhu^2,3,4,† , Tongyue Wang^5,† , Mingfu Liang^3,4 , Yue Yao^2,3,4 , Kairan Zhang^3,4 , Jizhong Zhang^3,4 , Hongyong Li^3,4 , Dongyang Han⁵ , Jishen Zheng⁶ , Brian Coventry^7,8 , Longxing Cao^2,4,7,8 , David Baker^7,8 , Lei Liu^5,* , Peilong Lu^2,3,4,*

¹College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China
²Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
³Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences and Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, China
⁴Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
⁵Tsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, China
⁶Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
⁷Department of Biochemistry, University of Washington, Seattle, WA, USA
⁸Institute for Protein Design, University of Washington, Seattle, WA, USA
^†These authors contributed equally: Ke Sun, Sicong Li, Bowen Zheng, Yanlei Zhu, Tongyue Wang
Correspondence: Lei Liu(lliu@mail.tsinghua.edu.cn)Peilong Lu(lupeilong@westlake.edu.cn)

Abiotic D-proteins that selectively bind to natural L-proteins have gained significant biotechnological interest. However, the underlying structural principles governing such heterochiral protein–protein interactions remain largely unknown. In this study, we present the de novo design of D-proteins consisting of 50–65 residues, aiming to target specific surface regions of L-proteins or L-peptides. Our designer D-protein binders exhibit nanomolar affinity toward an artificial L-peptide, as well as two naturally occurring proteins of therapeutic significance: the D5 domain of human tropomyosin receptor kinase A (TrkA) and human interleukin-6 (IL-6). Notably, these D-protein binders demonstrate high enantiomeric specificity and target specificity. In cell-based experiments, designer D-protein binders effectively inhibited the downstream signaling of TrkA and IL-6 with high potency. Moreover, these binders exhibited remarkable thermal stability and resistance to protease degradation. Crystal structure of the designed heterochiral D-protein–L-peptide complex, obtained at a resolution of 2.0 Å, closely resembled the design model, indicating that the computational method employed is highly accurate. Furthermore, the crystal structure provides valuable information regarding the interactions between helical L-peptides and D-proteins, particularly elucidating a novel mode of heterochiral helix–helix interactions....

https://doi.org/10.1038/s41422-024-01014-2

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