IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-49625-y.html
   My bibliography  Save this article

The binding mechanism of an anti-multiple myeloma antibody to the human GPRC5D homodimer

Author

Listed:
  • Pengfei Yan

    (ShanghaiTech University
    ShanghaiTech University)

  • Xi Lin

    (ShanghaiTech University)

  • Lijie Wu

    (ShanghaiTech University)

  • Lu Xu

    (ShanghaiTech University
    JiKang Therapeutics)

  • Fei Li

    (ShanghaiTech University)

  • Junlin Liu

    (ShanghaiTech University)

  • Fei Xu

    (ShanghaiTech University
    ShanghaiTech University
    Shanghai Clinical Research and Trial Center)

Abstract

GPRC5D is an atypical Class C orphan G protein-coupled receptor. Its high expression on the surface of multiple myeloma cells has rendered it an attractive target for therapeutic interventions, including monoclonal antibodies, CAR-T cells, and T-cell engagers. Despite its therapeutic potential, the insufficient understanding regarding of the receptor’s structure and antibody recognition mechanism has impeded the progress of effective therapeutic development. Here, we present the structure of GPRC5D in complex with a preclinical-stage single-chain antibody (scFv). Our structural analysis reveals that the GPRC5D presents a close resemblance to the typical Class C GPCRs in the transmembrane region. We identify a distinct head-to-head homodimer arrangement and interface mainly involving TM4, setting it apart from other Class C homo- or hetero-dimers. Furthermore, we elucidate the binding site engaging a sizable extracellular domain on GPRC5D for scFv recognition. These insights not only unveil the distinctive dimer organization of this unconventional Class C GPCR but also hold the potential to advance drug development targeting GPRC5D for the treatment of multiple myeloma.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49625-y
    DOI: 10.1038/s41467-024-49625-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-49625-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-49625-y?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. Antoine Koehl & Hongli Hu & Dan Feng & Bingfa Sun & Yan Zhang & Michael J. Robertson & Matthew Chu & Tong Sun Kobilka & Toon Laeremans & Jan Steyaert & Jeffrey Tarrasch & Somnath Dutta & Rasmus Fonsec, 2019. "Author Correction: Structural insights into the activation of metabotropic glutamate receptors," Nature, Nature, vol. 567(7747), pages 10-10, March.
    2. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    3. Antoine Koehl & Hongli Hu & Dan Feng & Bingfa Sun & Yan Zhang & Michael J. Robertson & Matthew Chu & Tong Sun Kobilka & Toon Laeremans & Jan Steyaert & Jeffrey Tarrasch & Somnath Dutta & Rasmus Fonsec, 2019. "Structural insights into the activation of metabotropic glutamate receptors," Nature, Nature, vol. 566(7742), pages 79-84, February.
    4. Xi Lin & Bo Chen & Yiran Wu & Yingqi Han & Ao Qi & Junyan Wang & Zhao Yang & Xiaohu Wei & Tingting Zhao & Lijie Wu & Xin Xie & Jinpeng Sun & Jie Zheng & Suwen Zhao & Fei Xu, 2023. "Cryo-EM structures of orphan GPR21 signaling complexes," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    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. Yang Gao & Michael J. Robertson & Sabrina N. Rahman & Alpay B. Seven & Chensong Zhang & Justin G. Meyerowitz & Ouliana Panova & Fadil M. Hannan & Rajesh V. Thakker & Hans Bräuner-Osborne & Jesper M. M, 2021. "Asymmetric activation of the calcium-sensing receptor homodimer," Nature, Nature, vol. 595(7867), pages 455-459, July.
    7. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    8. Heng Liu & Qing Zhang & Xinheng He & Mengting Jiang & Siwei Wang & Xiaoci Yan & Xi Cheng & Yang Liu & Fa-Jun Nan & H. Eric Xu & Xin Xie & Wanchao Yin, 2023. "Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    9. Geng Chen & Jun Xu & Asuka Inoue & Maximilian F. Schmidt & Chen Bai & Qiuyuan Lu & Peter Gmeiner & Zheng Liu & Yang Du, 2022. "Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    10. Juan Du & Dejian Wang & Hongcheng Fan & Chanjuan Xu & Linhua Tai & Shuling Lin & Shuo Han & Qiuxiang Tan & Xinwei Wang & Tuo Xu & Hui Zhang & Xiaojing Chu & Cuiying Yi & Peng Liu & Xiaomei Wang & Yu Z, 2021. "Structures of human mGlu2 and mGlu7 homo- and heterodimers," Nature, Nature, vol. 594(7864), pages 589-593, June.
    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. 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.
    3. Kaihua Zhang & Hao Wu & Nicholas Hoppe & Aashish Manglik & Yifan Cheng, 2022. "Fusion protein strategies for cryo-EM study of G protein-coupled receptors," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    4. 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.
    5. 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.
    6. Yingying Nie & Zeming Qiu & Sijia Chen & Zhao Chen & Xiaocui Song & Yan Ma & Niu Huang & Jason G. Cyster & Sanduo Zheng, 2023. "Specific binding of GPR174 by endogenous lysophosphatidylserine leads to high constitutive Gs signaling," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    7. 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.
    8. 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.
    9. 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.
    10. 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.
    11. Xinheng He & Lifen Zhao & Yinping Tian & Rui Li & Qinyu Chu & Zhiyong Gu & Mingyue Zheng & Yusong Wang & Shaoning Li & Hualiang Jiang & Yi Jiang & Liuqing Wen & Dingyan Wang & Xi Cheng, 2024. "Highly accurate carbohydrate-binding site prediction with DeepGlycanSite," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    12. 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.
    13. 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.
    14. Pierre Azoulay & Joshua Krieger & Abhishek Nagaraj, 2024. "Old Moats for New Models: Openness, Control, and Competition in Generative AI," NBER Chapters, in: Entrepreneurship and Innovation Policy and the Economy, volume 4, National Bureau of Economic Research, Inc.
    15. Jun-Yu Si & Yuan-Mei Chen & Ye-Hui Sun & Meng-Xue Gu & Mei-Ling Huang & Lu-Lu Shi & Xiao Yu & Xiao Yang & Qing Xiong & Cheng-Bao Ma & Peng Liu & Zheng-Li Shi & Huan Yan, 2024. "Sarbecovirus RBD indels and specific residues dictating multi-species ACE2 adaptiveness," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    16. Deyun Qiu & Jinxin V. Pei & James E. O. Rosling & Vandana Thathy & Dongdi Li & Yi Xue & John D. Tanner & Jocelyn Sietsma Penington & Yi Tong Vincent Aw & Jessica Yi Han Aw & Guoyue Xu & Abhai K. Tripa, 2022. "A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    17. Shuo-Shuo Liu & Tian-Xia Jiang & Fan Bu & Ji-Lan Zhao & Guang-Fei Wang & Guo-Heng Yang & Jie-Yan Kong & Yun-Fan Qie & Pei Wen & Li-Bin Fan & Ning-Ning Li & Ning Gao & Xiao-Bo Qiu, 2024. "Molecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    18. Xiaoke Yang & Mingqi Zhu & Xue Lu & Yuxin Wang & Junyu Xiao, 2024. "Architecture and activation of human muscle phosphorylase kinase," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    19. Efren Garcia-Maldonado & Andrew D. Huber & Sergio C. Chai & Stanley Nithianantham & Yongtao Li & Jing Wu & Shyaron Poudel & Darcie J. Miller & Jayaraman Seetharaman & Taosheng Chen, 2024. "Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    20. Kristy Rochon & Brianna L. Bauer & Nathaniel A. Roethler & Yuli Buckley & Chih-Chia Su & Wei Huang & Rajesh Ramachandran & Maria S. K. Stoll & Edward W. Yu & Derek J. Taylor & Jason A. Mears, 2024. "Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1," Nature Communications, Nature, vol. 15(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:15:y:2024:i:1:d:10.1038_s41467-024-49625-y. 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.