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Distinct oligomeric assemblies of STING induced by non-nucleotide agonists

Author

Listed:
  • Anant Gharpure

    (Scripps Research)

  • Ariana Sulpizio

    (Scripps Research)

  • Johannes R. Loeffler

    (Scripps Research)

  • Monica L. Fernández-Quintero

    (Scripps Research)

  • Andy S. Tran

    (Scripps Research)

  • Luke L. Lairson

    (Scripps Research)

  • Andrew B. Ward

    (Scripps Research)

Abstract

STING plays essential roles coordinating innate immune responses to processes that range from pathogenic infection to genomic instability. Its adaptor function is activated by cyclic dinucleotide (CDN) secondary messengers originating from self (2’3’-cGAMP) or bacterial sources (3’3’-CDNs). Different classes of CDNs possess distinct binding modes, stabilizing STING’s ligand-binding domain (LBD) in either a closed or open conformation. The closed conformation, induced by the endogenous ligand 2’3’-cGAMP, has been extensively studied using cryo-EM. However, significant questions remain regarding the structural basis of STING activation by open conformation-inducing ligands. Using cryo-EM, we investigate potential differences in conformational changes and oligomeric assemblies of STING for closed and open conformation-inducing synthetic agonists. While we observe a characteristic 180° rotation for both classes, the open-LBD inducing agonist diABZI-3 uniquely induces a quaternary structure reminiscent but distinct from the reported autoinhibited state of apo-STING. Additionally, we observe slower rates of activation for this ligand class in functional assays, which collectively suggests the existence of a potential additional regulatory mechanism for open conformation-inducing ligands that involves head-to-head interactions and restriction of curved oligomer formation. These observations have potential implications in the selection of an optimal class of STING agonist in the context of a defined therapeutic application.

Suggested Citation

  • Anant Gharpure & Ariana Sulpizio & Johannes R. Loeffler & Monica L. Fernández-Quintero & Andy S. Tran & Luke L. Lairson & Andrew B. Ward, 2025. "Distinct oligomeric assemblies of STING induced by non-nucleotide agonists," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58641-5
    DOI: 10.1038/s41467-025-58641-5
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    References listed on IDEAS

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    1. Xiang Gui & Hui Yang & Tuo Li & Xiaojun Tan & Peiqing Shi & Minghao Li & Fenghe Du & Zhijian J. Chen, 2019. "Autophagy induction via STING trafficking is a primordial function of the cGAS pathway," Nature, Nature, vol. 567(7747), pages 262-266, March.
    2. Dara L. Burdette & Kathryn M. Monroe & Katia Sotelo-Troha & Jeff S. Iwig & Barbara Eckert & Mamoru Hyodo & Yoshihiro Hayakawa & Russell E. Vance, 2011. "STING is a direct innate immune sensor of cyclic di-GMP," Nature, Nature, vol. 478(7370), pages 515-518, October.
    3. Andrea Ablasser & Marion Goldeck & Taner Cavlar & Tobias Deimling & Gregor Witte & Ingo Röhl & Karl-Peter Hopfner & Janos Ludwig & Veit Hornung, 2013. "cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING," Nature, Nature, vol. 498(7454), pages 380-384, June.
    4. Qing Chen & Adrienne Boire & Xin Jin & Manuel Valiente & Ekrem Emrah Er & Alejandro Lopez-Soto & Leni S. Jacob & Ruzeen Patwa & Hardik Shah & Ke Xu & Justin R. Cross & Joan Massagué, 2016. "Carcinoma–astrocyte gap junctions promote brain metastasis by cGAMP transfer," Nature, Nature, vol. 533(7604), pages 493-498, May.
    5. Guijun Shang & Conggang Zhang & Zhijian J. Chen & Xiao-chen Bai & Xuewu Zhang, 2019. "Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP–AMP," Nature, Nature, vol. 567(7748), pages 389-393, March.
    6. Joshi M. Ramanjulu & G. Scott Pesiridis & Jingsong Yang & Nestor Concha & Robert Singhaus & Shu-Yun Zhang & Jean-Luc Tran & Patrick Moore & Stephanie Lehmann & H. Christian Eberl & Marcel Muelbaier & , 2018. "Design of amidobenzimidazole STING receptor agonists with systemic activity," Nature, Nature, vol. 564(7736), pages 439-443, December.
    7. Hiroki Ishikawa & Glen N. Barber, 2008. "Erratum: STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling," Nature, Nature, vol. 456(7219), pages 274-274, November.
    8. Seung-hwan Jeong & Myung Jin Yang & Seunghyeok Choi & JungMo Kim & Gou Young Koh, 2021. "Refractoriness of STING therapy is relieved by AKT inhibitor through effective vascular disruption in tumour," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    9. Conggang Zhang & Guijun Shang & Xiang Gui & Xuewu Zhang & Xiao-chen Bai & Zhijian J. Chen, 2019. "Structural basis of STING binding with and phosphorylation by TBK1," Nature, Nature, vol. 567(7748), pages 394-398, March.
    10. Defen Lu & Guijun Shang & Jie Li & Yong Lu & Xiao-chen Bai & Xuewu Zhang, 2022. "Activation of STING by targeting a pocket in the transmembrane domain," Nature, Nature, vol. 604(7906), pages 557-562, April.
    11. Hiroki Ishikawa & Glen N. Barber, 2008. "STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling," Nature, Nature, vol. 455(7213), pages 674-678, October.
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