IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-32213-3.html
   My bibliography  Save this article

G protein coupling and activation of the metabotropic GABAB heterodimer

Author

Listed:
  • Moon Young Yang

    (California Institute of Technology)

  • Soo-Kyung Kim

    (California Institute of Technology)

  • William A. Goddard

    (California Institute of Technology)

Abstract

Metabotropic γ-aminobutyric acid receptor (GABABR), a class C G protein-coupled receptor (GPCR) heterodimer, plays a crucial role in the central nervous system. Cryo-electron microscopy studies revealed a drastic conformational change upon activation and a unique G protein (GP) binding mode. However, little is known about the mechanism for GP coupling and activation for class C GPCRs. Here, we use molecular metadynamics computations to predict the mechanism by which the inactive GP induces conformational changes in the GABABR transmembrane domain (TMD) to form an intermediate pre-activated state. We find that the inactive GP first interacts with TM3, which further leads to the TMD rearrangement and deeper insertion of the α5 helix that causes the Gα subunit to open, releasing GDP, and forming the experimentally observed activated structure. This mechanism provides fresh insights into the mechanistic details of class C GPCRs activation expected to be useful for designing selective agonists and antagonists.

Suggested Citation

  • Moon Young Yang & Soo-Kyung Kim & William A. Goddard, 2022. "G protein coupling and activation of the metabotropic GABAB heterodimer," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32213-3
    DOI: 10.1038/s41467-022-32213-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-32213-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-32213-3?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. Cangsong Shen & Chunyou Mao & Chanjuan Xu & Nan Jin & Huibing Zhang & Dan-Dan Shen & Qingya Shen & Xiaomei Wang & Tingjun Hou & Zhong Chen & Philippe Rondard & Jean-Philippe Pin & Yan Zhang & Jianfeng, 2021. "Structural basis of GABAB receptor–Gi protein coupling," Nature, Nature, vol. 594(7864), pages 594-598, June.
    2. Vaithish Velazhahan & Ning Ma & Nagarajan Vaidehi & Christopher G. Tate, 2022. "Activation mechanism of the class D fungal GPCR dimer Ste2," Nature, Nature, vol. 603(7902), pages 743-748, March.
    3. Yong Geng & Martin Bush & Lidia Mosyak & Feng Wang & Qing R. Fan, 2013. "Structural mechanism of ligand activation in human GABAB receptor," Nature, Nature, vol. 504(7479), pages 254-259, December.
    4. Hamidreza Shaye & Andrii Ishchenko & Jordy Homing Lam & Gye Won Han & Li Xue & Philippe Rondard & Jean-Philippe Pin & Vsevolod Katritch & Cornelius Gati & Vadim Cherezov, 2020. "Structural basis of the activation of a metabotropic GABA receptor," Nature, Nature, vol. 584(7820), pages 298-303, August.
    5. Alpay B. Seven & Ximena Barros-Álvarez & Marine Lapeyrière & Makaía M. Papasergi-Scott & Michael J. Robertson & Chensong Zhang & Robert M. Nwokonko & Yang Gao & Justin G. Meyerowitz & Jean-Philippe Ro, 2021. "G-protein activation by a metabotropic glutamate receptor," Nature, Nature, vol. 595(7867), pages 450-454, July.
    6. Jinseo Park & Ziao Fu & Aurel Frangaj & Jonathan Liu & Lidia Mosyak & Tong Shen & Vesna N. Slavkovich & Kimberly M. Ray & Jaume Taura & Baohua Cao & Yong Geng & Hao Zuo & Yongjun Kou & Robert Grassucc, 2020. "Author Correction: Structure of human GABAB receptor in an inactive state," Nature, Nature, vol. 583(7818), pages 29-29, July.
    7. Jinseo Park & Ziao Fu & Aurel Frangaj & Jonathan Liu & Lidia Mosyak & Tong Shen & Vesna N. Slavkovich & Kimberly M. Ray & Jaume Taura & Baohua Cao & Yong Geng & Hao Zuo & Yongjun Kou & Robert Grassucc, 2020. "Structure of human GABAB receptor in an inactive state," Nature, Nature, vol. 584(7820), pages 304-309, August.
    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. Yaejin Yun & Hyeongseop Jeong & Thibaut Laboute & Kirill A. Martemyanov & Hyung Ho Lee, 2024. "Cryo-EM structure of human class C orphan GPCR GPR179 involved in visual processing," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Eunyoung Jeong & Yoojoong Kim & Jihong Jeong & Yunje Cho, 2021. "Structure of the class C orphan GPCR GPR158 in complex with RGS7-Gβ5," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    3. Marie-Lise Jobin & Sana Siddig & Zsombor Koszegi & Yann Lanoiselée & Vladimir Khayenko & Titiwat Sungkaworn & Christian Werner & Kerstin Seier & Christin Misigaiski & Giovanna Mantovani & Markus Sauer, 2023. "Filamin A organizes γ‑aminobutyric acid type B receptors at the plasma membrane," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Alexa Strauss & Alberto J. Gonzalez-Hernandez & Joon Lee & Nohely Abreu & Purushotham Selvakumar & Leslie Salas-Estrada & Melanie Kristt & Anisul Arefin & Kevin Huynh & Dagan C. Marx & Kristen Gillila, 2024. "Structural basis of positive allosteric modulation of metabotropic glutamate receptor activation and internalization," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Michael R. Schamber & Reza Vafabakhsh, 2022. "Mechanism of sensitivity modulation in the calcium-sensing receptor via electrostatic tuning," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    6. Xin Lin & Davide Provasi & Colleen M. Niswender & Wesley B. Asher & Jonathan A. Javitch, 2024. "Elucidating the molecular logic of a metabotropic glutamate receptor heterodimer," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    7. Chanjuan Xu & Yiwei Zhou & Yuxuan Liu & Li Lin & Peng Liu & Xiaomei Wang & Zhengyuan Xu & Jean-Philippe Pin & Philippe Rondard & Jianfeng Liu, 2024. "Specific pharmacological and Gi/o protein responses of some native GPCRs in neurons," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    8. Junke Liu & Hengmin Tang & Chanjuan Xu & Shengnan Zhou & Xunying Zhu & Yuanyuan Li & Laurent Prézeau & Tao Xu & Jean-Philippe Pin & Philippe Rondard & Wei Ji & Jianfeng Liu, 2022. "Biased signaling due to oligomerization of the G protein-coupled platelet-activating factor receptor," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    9. Julien Bous & Julia Kinsolving & Lukas Grätz & Magdalena M. Scharf & Jan Hendrik Voss & Berkay Selcuk & Ogün Adebali & Gunnar Schulte, 2024. "Structural basis of frizzled 7 activation and allosteric regulation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    10. Janik B. Hedderich & Margherita Persechino & Katharina Becker & Franziska M. Heydenreich & Torben Gutermuth & Michel Bouvier & Moritz Bünemann & Peter Kolb, 2022. "The pocketome of G-protein-coupled receptors reveals previously untargeted allosteric sites," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    11. Pengfei Yan & Xi Lin & Lijie Wu & Lu Xu & Fei Li & Junlin Liu & Fei Xu, 2024. "The binding mechanism of an anti-multiple myeloma antibody to the human GPRC5D homodimer," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    12. Chris Habrian & Naomi Latorraca & Zhu Fu & Ehud Y. Isacoff, 2023. "Homo- and hetero-dimeric subunit interactions set affinity and efficacy in metabotropic glutamate receptors," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    13. T. Bertie Ansell & Wanling Song & Claire E. Coupland & Loic Carrique & Robin A. Corey & Anna L. Duncan & C. Keith Cassidy & Maxwell M. G. Geurts & Tim Rasmussen & Andrew B. Ward & Christian Siebold & , 2023. "LipIDens: simulation assisted interpretation of lipid densities in cryo-EM structures of membrane proteins," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    14. Kento Ojima & Wataru Kakegawa & Tokiwa Yamasaki & Yuta Miura & Masayuki Itoh & Yukiko Michibata & Ryou Kubota & Tomohiro Doura & Eriko Miura & Hiroshi Nonaka & Seiya Mizuno & Satoru Takahashi & Michis, 2022. "Coordination chemogenetics for activation of GPCR-type glutamate receptors in brain tissue," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    15. Chunyou Mao & Mengru Gao & Shao-Kun Zang & Yanqing Zhu & Dan-Dan Shen & Li-Nan Chen & Liu Yang & Zhiwei Wang & Huibing Zhang & Wei-Wei Wang & Qingya Shen & Yanhui Lu & Xin Ma & Yan Zhang, 2023. "Orthosteric and allosteric modulation of human HCAR2 signaling complex," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    16. Yu Qian & Zhengxiong Ma & Zhenmei Xu & Yaning Duan & Yangjie Xiong & Ruixue Xia & Xinyan Zhu & Zongwei Zhang & Xinyu Tian & Han Yin & Jian Liu & Jing Song & Yang Lu & Anqi Zhang & Changyou Guo & Lihua, 2024. "Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    17. Mingyu Li & Xiaobing Lan & Xinchao Shi & Chunhao Zhu & Xun Lu & Jun Pu & Shaoyong Lu & Jian Zhang, 2024. "Delineating the stepwise millisecond allosteric activation mechanism of the class C GPCR dimer mGlu5," Nature Communications, Nature, vol. 15(1), pages 1-14, 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:13:y:2022:i:1:d:10.1038_s41467-022-32213-3. 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.