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Structural basis of agonist specificity of α1A-adrenergic receptor

Author

Listed:
  • Minfei Su

    (Weill Cornell Medical College of Cornell University)

  • Jinan Wang

    (University of Kansas)

  • Guoqing Xiang

    (Weill Cornell Medical College of Cornell University
    Weill Cornell Medical College of Cornell University)

  • Hung Nguyen Do

    (University of Kansas)

  • Joshua Levitz

    (Weill Cornell Medical College of Cornell University
    Weill Cornell Medical College of Cornell University)

  • Yinglong Miao

    (University of Kansas)

  • Xin-Yun Huang

    (Weill Cornell Medical College of Cornell University)

Abstract

α1-adrenergic receptors (α1-ARs) play critical roles in the cardiovascular and nervous systems where they regulate blood pressure, cognition, and metabolism. However, the lack of specific agonists for all α1 subtypes has limited our understanding of the physiological roles of different α1-AR subtypes, and led to the stagnancy in agonist-based drug development for these receptors. Here we report cryo-EM structures of α1A-AR in complex with heterotrimeric G-proteins and either the endogenous common agonist epinephrine or the α1A-AR-specific synthetic agonist A61603. These structures provide molecular insights into the mechanisms underlying the discrimination between α1A-AR and α1B-AR by A61603. Guided by the structures and corresponding molecular dynamics simulations, we engineer α1A-AR mutants that are not responsive to A61603, and α1B-AR mutants that can be potently activated by A61603. Together, these findings advance our understanding of the agonist specificity for α1-ARs at the molecular level, opening the possibility of rational design of subtype-specific agonists.

Suggested Citation

  • Minfei Su & Jinan Wang & Guoqing Xiang & Hung Nguyen Do & Joshua Levitz & Yinglong Miao & Xin-Yun Huang, 2023. "Structural basis of agonist specificity of α1A-adrenergic receptor," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40524-2
    DOI: 10.1038/s41467-023-40524-2
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    References listed on IDEAS

    as
    1. Shian Liu & Navid Paknejad & Lan Zhu & Yasuyuki Kihara & Manisha Ray & Jerold Chun & Wei Liu & Richard K. Hite & Xin-Yun Huang, 2022. "Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Aaron M. Ring & Aashish Manglik & Andrew C. Kruse & Michael D. Enos & William I. Weis & K. Christopher Garcia & Brian K. Kobilka, 2013. "Adrenaline-activated structure of β2-adrenoceptor stabilized by an engineered nanobody," Nature, Nature, vol. 502(7472), pages 575-579, October.
    3. Minfei Su & Navid Paknejad & Lan Zhu & Jinan Wang & Hung Nguyen Do & Yinglong Miao & Wei Liu & Richard K. Hite & Xin-Yun Huang, 2022. "Structures of β1-adrenergic receptor in complex with Gs and ligands of different efficacies," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
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