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

Cell Research (2026)Cite this article

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Abstract

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.

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Fig. 1: A comprehensive and well-resolved phylogeny of 4854 insects.
Fig. 2: The insect protein-structure universe and statistics.
Fig. 3: Insect functional genomics.
Fig. 4: Structural alignments reveal massive numbers of remote homologous proteins across the insect tree of life.
Fig. 5: A notable case of remote homologs: cGLRs are structurally conserved but show marked sequence divergence across the insect tree of life, with functional characterization in the yellow fever mosquito.

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Data availability

All gene alignments and gene trees are available on the figshare repository (https://doi.org/10.25452/figshare.plus.25906339). Raw RNA sequencing data has been deposited in GenBank under Bioproject ID: PRJNA1173893. Protein structures are freely available on TIPS database (http://tips.shenxlab.com/). The web server offers options for searching, visualizing, and downloading protein structures, as well as accessing the comprehensive insect tree of life.

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Acknowledgements

We thank Antonis Rokas for insightful comments and Xin Qiao for help with the cell culture and transfection. This work was conducted in part using the resources of the Information Technology Center and State Key Lab of CAD&CG at Zhejiang University. This work was supported by the Scientific Research Innovation Capability Support Project for Young Faculty (ZYGXQNJSKYCXNLZCXM-A12 to X.-X.S.), the Key Program of National Natural Science Foundation of China (32530086 to X.-X.S.), the National Science Foundation for Distinguished Young Scholars of Zhejiang Province (LR23C140001 to X.-X.S.), Shanghai Municipal Science and Technology Major Project (S.W.), the New Cornerstone Science Foundation (NCI202328 to S.W.), the National Natural Science Foundation of China (32230015 and 32021001 to S.W., 32200395 to C.C.), Zhejiang Provincial Natural Science Foundation of China (LZ23C020002 to R.P.), the Key-Area Research and Development Program of Guangdong Province (2018B020205003 and 2020B0202090001 to X.Z.), and the Key International Joint Research Program of National Natural Science Foundation of China (31920103005 to X.-X.C.).

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Author notes

  1. These authors contributed equally: Weiyin Wu, Chunlai Cui, Yixiao Zhu.

Authors and Affiliations

  1. Zhejiang 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

    Weiyin Wu, Yixiao Zhu, Jingxuan Chen, Qiancheng Zhuang, Yazhou Wang, Guo-Zheng Ou, Chao Liu, Mei Tao, Yun Chen, Jinghua Yang, Xue-xin Chen & Xing-Xing Shen

  2. New 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

    Chunlai Cui, Zicheng Liu, Han Gao & Sibao Wang

  3. Shanghai Institute of Wildlife Epidemics, School of Life Sciences, East China Normal University, Shanghai, China

    Chunlai Cui

  4. Hainan Institute, Zhejiang University, Yazhou Bay Science and Technology City, Sanya, Hainan, China

    Yixiao Zhu, Jinghua Yang & Xing-Xing Shen

  5. ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, Zhejiang, China

    Ronghui Pan

  6. Centre for Evolutionary & Organismal Biology, Zhejiang University, Hangzhou, Zhejiang, China

    Guojie Zhang & Xing-Xing Shen

  7. Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, Guangdong, China

    Hua Cai

  8. Guangdong 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

    Xiaofan Zhou

Authors
  1. Weiyin Wu
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  2. Chunlai Cui
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  3. Yixiao Zhu
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  6. Yazhou Wang
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  20. Xing-Xing Shen
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Contributions

X.-X.S. and S.W. conceived and designed the study. X.-X.S., W.W., C.C., Y.Z., J.C., Q.Z., Y.W., H.C., Z.L., H.G., G.-Z.O., C.L., and M.T. performed computational analyses and experiments. X.-X.S., S.W., W.W., C.C., Y.Z., X.Z., Y.C., R.P., J.Y., H.C., G.Z., and X.-X.C. interpreted results. X.-X.S. wrote the manuscript with input from all authors. X.-X.S., S.W., W.W., C.C., X.Z., and H.C. edited the manuscript.

Corresponding authors

Correspondence to Xiaofan Zhou, Sibao Wang or Xing-Xing Shen.

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Wu, W., Cui, C., Zhu, Y. et al. Structural genomics sheds light on protein functions and remote homologs across the insect tree of life. Cell Res (2026). https://doi.org/10.1038/s41422-026-01220-0

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