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Structural genomics sheds light on protein functions and remote homologs across the insect tree of life

Weiyin Wu^1,† , Chunlai Cui^2,3,† , Yixiao Zhu^1,4,† , Jingxuan Chen¹ , Qiancheng Zhuang¹ , Yazhou Wang¹ , Zicheng Liu² , Han Gao² , Guo-Zheng Ou¹ , Chao Liu¹ , Mei Tao¹ , Yun Chen¹ , Ronghui Pan⁵ , Guojie Zhang⁶ , Hua Cai⁷ , Jinghua Yang^1,4 , Xue-xin Chen¹ , Xiaofan Zhou^8,* , Sibao Wang^2,* , Xing-Xing Shen^1,4,6,*

¹Zhejiang Key Laboratory of Biology and Ecological Regulation of Crop Pathogens and Insects, State Key Laboratory for Vegetation Structure, Function and Construction, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, Zhejiang, China
²New Cornerstone Science Laboratory, Key Laboratory of Insect Developmental and Evolutionary Biology, State Key Laboratory of Plant Trait Design, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, China
³Shanghai Institute of Wildlife Epidemics, School of Life Sciences, East China Normal University, Shanghai, China
⁴Hainan Institute, Zhejiang University, Yazhou Bay Science and Technology City, Sanya, Hainan, China
⁵ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, Zhejiang, China
⁶Centre for Evolutionary & Organismal Biology, Zhejiang University, Hangzhou, Zhejiang, China
⁷Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, Guangdong, China
⁸Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, Integrative Microbiology Research Centre, South China Agricultural University, Guangzhou, Guangdong, China
^†These authors contributed equally: Weiyin Wu, Chunlai Cui, Yixiao Zhu
* Correspondence: Xiaofan Zhou(xiaofan_zhou@scau.edu.cn)Sibao Wang(sbwang@cemps.ac.cn)Xing-Xing Shen(xingxingshen@zju.edu.cn)

Protein structure bridges the sequence–function relationship, enabling deep exploration of biological processes across diverse organisms. Insects, the most diverse animal lineage, accounting for over 50% of all described animal species, provide an exceptional system for exploring sequence–structure–function relationships. Here, we reconstructed a comprehensive and well-resolved phylogeny of 4854 insects, spanning all orders. Leveraging this framework, we created an atlas of 13.29 million predicted protein structures from 824 representative species, including 11.63 million newly predicted structures. Structural clustering revealed that proteins with divergent sequences but similar structures could be effectively grouped together. Structural similarity searches against proteins with well-characterized functions yielded annotations for 7.61 million insect proteins, including up to 14% of previously unannotated proteins. We further identified 750 million remote homologs between insect proteins, many of which trace back to ancient branches of the insect phylogeny. Remarkably, despite extensive sequence divergence, cGAS-like receptors (cGLRs) were structurally conserved across all 824 insects. Experimental assays demonstrated that these structurally identified cGLRs play a crucial role in antiviral defense in the yellow fever mosquito. Our findings highlight the significance of structural genomics for understanding protein function and evolution across the tree of life.

https://doi.org/10.1038/s41422-026-01220-0

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