IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-40524-2.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-40524-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-40524-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Navid Paknejad & Vinay Sapuru & Richard K. Hite, 2023. "Structural titration reveals Ca2+-dependent conformational landscape of the IP3 receptor," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Xuan Zhang & Yujing Wang & Shreyas Supekar & Xu Cao & Jingkai Zhou & Jessica Dang & Siqi Chen & Laura Jenkins & Sara Marsango & Xiu Li & Guibing Liu & Graeme Milligan & Mingye Feng & Hao Fan & Weimin , 2023. "Pro-phagocytic function and structural basis of GPR84 signaling," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Yosuke Toyoda & Angqi Zhu & Fang Kong & Sisi Shan & Jiawei Zhao & Nan Wang & Xiaoou Sun & Linqi Zhang & Chuangye Yan & Brian K. Kobilka & Xiangyu Liu, 2023. "Structural basis of α1A-adrenergic receptor activation and recognition by an extracellular nanobody," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. Hiroaki Akasaka & Tatsuki Tanaka & Fumiya K. Sano & Yuma Matsuzaki & Wataru Shihoya & Osamu Nureki, 2022. "Structure of the active Gi-coupled human lysophosphatidic acid receptor 1 complexed with a potent agonist," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    5. Andrew J. Y. Jones & Thomas H. Harman & Matthew Harris & Oliver E. Lewis & Graham Ladds & Daniel Nietlispach, 2024. "Binding kinetics drive G protein subtype selectivity at the β1-adrenergic receptor," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    6. Tamaki Izume & Ryo Kawahara & Akiharu Uwamizu & Luying Chen & Shun Yaginuma & Jumpei Omi & Hiroki Kawana & Fengjue Hou & Fumiya K. Sano & Tatsuki Tanaka & Kazuhiro Kobayashi & Hiroyuki H. Okamoto & Yo, 2024. "Structural basis for lysophosphatidylserine recognition by GPR34," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    7. Xin Chen & Kexin Wang & Jianfang Chen & Chao Wu & Jun Mao & Yuanpeng Song & Yijing Liu & Zhenhua Shao & Xuemei Pu, 2024. "Integrative residue-intuitive machine learning and MD Approach to Unveil Allosteric Site and Mechanism for β2AR," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    8. Jie Heng & Yunfei Hu & Guillermo Pérez-Hernández & Asuka Inoue & Jiawei Zhao & Xiuyan Ma & Xiaoou Sun & Kouki Kawakami & Tatsuya Ikuta & Jienv Ding & Yujie Yang & Lujia Zhang & Sijia Peng & Xiaogang N, 2023. "Function and dynamics of the intrinsically disordered carboxyl terminus of β2 adrenergic receptor," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    9. Xinyu Xu & Jeremy Shonberg & Jonas Kaindl & Mary J. Clark & Anne Stößel & Luis Maul & Daniel Mayer & Harald Hübner & Kunio Hirata & A. J. Venkatakrishnan & Ron O. Dror & Brian K. Kobilka & Roger K. Su, 2023. "Constrained catecholamines gain β2AR selectivity through allosteric effects on pocket dynamics," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    10. Jiale Liang & Asuka Inoue & Tatsuya Ikuta & Ruixue Xia & Na Wang & Kouki Kawakami & Zhenmei Xu & Yu Qian & Xinyan Zhu & Anqi Zhang & Changyou Guo & Zhiwei Huang & Yuanzheng He, 2023. "Structural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation," Nature Communications, Nature, vol. 14(1), pages 1-10, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40524-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.