IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-50642-0.html
   My bibliography  Save this article

Dual-site molecular glues for enhancing protein-protein interactions of the CDK12-DDB1 complex

Author

Listed:
  • Zemin Zhang

    (Fujian Medical University)

  • Yuanqing Li

    (Nanjing University of Chinese Medicine
    Chinese Academy of Sciences)

  • Jie Yang

    (Fujian Normal University)

  • Jiacheng Li

    (Chinese Academy of Sciences)

  • Xiongqiang Lin

    (Fujian Medical University)

  • Ting Liu

    (Fujian Medical University)

  • Shiling Yang

    (Fujian Normal University)

  • Jin Lin

    (Fujian Medical University)

  • Shengyu Xue

    (Nanjing University of Chinese Medicine
    Chinese Academy of Sciences)

  • Jiamin Yu

    (Nanjing University of Chinese Medicine
    Chinese Academy of Sciences)

  • Cailing Tang

    (Nanjing University of Chinese Medicine
    Chinese Academy of Sciences)

  • Ziteng Li

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Liping Liu

    (Chinese Academy of Sciences)

  • Zhengzheng Ye

    (University of Chinese Academy of Sciences)

  • Yanan Deng

    (University of Chinese Academy of Sciences)

  • Zhihai Li

    (University of Chinese Academy of Sciences)

  • Kaixian Chen

    (Nanjing University of Chinese Medicine
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Hong Ding

    (Chinese Academy of Sciences
    Guizhou Medical University)

  • Cheng Luo

    (Fujian Medical University
    Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Hua Lin

    (Chinese Academy of Sciences
    Fujian Normal University
    Chinese Academy of Sciences)

Abstract

Protein-protein interactions (PPIs) stabilization with molecular glues plays a crucial role in drug discovery, albeit with significant challenges. In this study, we propose a dual-site approach, targeting the PPI region and its dynamic surroundings. We conduct molecular dynamics simulations to identify critical sites on the PPI that stabilize the cyclin-dependent kinase 12 - DNA damage-binding protein 1 (CDK12-DDB1) complex, resulting in further cyclin K degradation. This exploration leads to the creation of LL-K12-18, a dual-site molecular glue, which enhances the glue properties to augment degradation kinetics and efficiency. Notably, LL-K12-18 demonstrates strong inhibition of gene transcription and anti-proliferative effects in tumor cells, showing significant potency improvements in MDA-MB-231 (88-fold) and MDA-MB-468 cells (307-fold) when compared to its precursor compound SR-4835. These findings underscore the potential of dual-site approaches in disrupting CDK12 function and offer a structural insight-based framework for the design of cyclin K molecular glues.

Suggested Citation

  • Zemin Zhang & Yuanqing Li & Jie Yang & Jiacheng Li & Xiongqiang Lin & Ting Liu & Shiling Yang & Jin Lin & Shengyu Xue & Jiamin Yu & Cailing Tang & Ziteng Li & Liping Liu & Zhengzheng Ye & Yanan Deng &, 2024. "Dual-site molecular glues for enhancing protein-protein interactions of the CDK12-DDB1 complex," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50642-0
    DOI: 10.1038/s41467-024-50642-0
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-50642-0
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-50642-0?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. Youyi Zhang & Fei Ye & Tongtong Zhang & Shiyun Lv & Liping Zhou & Daohai Du & He Lin & Fei Guo & Cheng Luo & Shujia Zhu, 2021. "Structural basis of ketamine action on human NMDA receptors," Nature, Nature, vol. 596(7871), pages 301-305, August.
    2. Mary E. Matyskiela & Gang Lu & Takumi Ito & Barbra Pagarigan & Chin-Chun Lu & Karen Miller & Wei Fang & Nai-Yu Wang & Derek Nguyen & Jack Houston & Gilles Carmel & Tam Tran & Mariko Riley & Lyn’Al Nos, 2016. "A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase," Nature, Nature, vol. 535(7611), pages 252-257, July.
    3. Eric S. Fischer & Kerstin Böhm & John R. Lydeard & Haidi Yang & Michael B. Stadler & Simone Cavadini & Jane Nagel & Fabrizio Serluca & Vincent Acker & Gondichatnahalli M. Lingaraju & Ritesh B. Tichkul, 2014. "Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide," Nature, Nature, vol. 512(7512), pages 49-53, August.
    4. Qiangfeng Cliff Zhang & Donald Petrey & Lei Deng & Li Qiang & Yu Shi & Chan Aye Thu & Brygida Bisikirska & Celine Lefebvre & Domenico Accili & Tony Hunter & Tom Maniatis & Andrea Califano & Barry Honi, 2012. "Structure-based prediction of protein–protein interactions on a genome-wide scale," Nature, Nature, vol. 490(7421), pages 556-560, October.
    5. Youyi Zhang & Fei Ye & Tongtong Zhang & Shiyun Lv & Liping Zhou & Daohai Du & He Lin & Fei Guo & Cheng Luo & Shujia Zhu, 2021. "Author Correction: Structural basis of ketamine action on human NMDA receptors," Nature, Nature, vol. 598(7882), pages 3-3, October.
    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. Satoshi Yamanaka & Hirotake Furihata & Yuta Yanagihara & Akihito Taya & Takato Nagasaka & Mai Usui & Koya Nagaoka & Yuki Shoya & Kohei Nishino & Shuhei Yoshida & Hidetaka Kosako & Masaru Tanokura & Ta, 2023. "Lenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Shiyun Cao & Shoukai Kang & Haibin Mao & Jiayu Yao & Liangcai Gu & Ning Zheng, 2022. "Defining molecular glues with a dual-nanobody cannabidiol sensor," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Jian Ma & Lei Li & Bohan Ma & Tianjie Liu & Zixi Wang & Qi Ye & Yunhua Peng & Bin Wang & Yule Chen & Shan Xu & Ke Wang & Fabin Dang & Xinyang Wang & Zixuan Zeng & Yanlin Jian & Zhihua Ren & Yizeng Fan, 2024. "MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Patrick Bryant & Gabriele Pozzati & Arne Elofsson, 2022. "Improved prediction of protein-protein interactions using AlphaFold2," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    5. Alena Kroupova & Valentina A. Spiteri & Zoe J. Rutter & Hirotake Furihata & Darren Darren & Sarath Ramachandran & Sohini Chakraborti & Kevin Haubrich & Julie Pethe & Denzel Gonzales & Andre J. Wijaya , 2024. "Design of a Cereblon construct for crystallographic and biophysical studies of protein degraders," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    6. Sarath Ramachandran & Nikolai Makukhin & Kevin Haubrich & Manjula Nagala & Beth Forrester & Dylan M. Lynch & Ryan Casement & Andrea Testa & Elvira Bruno & Rosaria Gitto & Alessio Ciulli, 2023. "Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    7. Josh N. Vo & Yi-Mi Wu & Jeanmarie Mishler & Sarah Hall & Rahul Mannan & Lisha Wang & Yu Ning & Jin Zhou & Alexander C. Hopkins & James C. Estill & Wallace K. B. Chan & Jennifer Yesil & Xuhong Cao & Ar, 2022. "The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    8. Yuen Lam Dora Ng & Evelyn Ramberger & Stephan R. Bohl & Anna Dolnik & Christian Steinebach & Theresia Conrad & Sina Müller & Oliver Popp & Miriam Kull & Mohamed Haji & Michael Gütschow & Hartmut Döhne, 2022. "Proteomic profiling reveals CDK6 upregulation as a targetable resistance mechanism for lenalidomide in multiple myeloma," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    9. Gisele Nishiguchi & Lauren G. Mascibroda & Sarah M. Young & Elizabeth A. Caine & Sherif Abdelhamed & Jeffrey J. Kooijman & Darcie J. Miller & Sourav Das & Kevin McGowan & Anand Mayasundari & Zhe Shi &, 2024. "Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    10. Daniel C. Scott & Suresh Dharuman & Elizabeth Griffith & Sergio C. Chai & Jarrid Ronnebaum & Moeko T. King & Rajendra Tangallapally & Chan Lee & Clifford T. Gee & Lei Yang & Yong Li & Victoria C. Loud, 2024. "Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    11. Jiahua Rao & Jiancong Xie & Qianmu Yuan & Deqin Liu & Zhen Wang & Yutong Lu & Shuangjia Zheng & Yuedong Yang, 2024. "A variational expectation-maximization framework for balanced multi-scale learning of protein and drug interactions," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    12. Zefeng Wang & Shabnam Shaabani & Xiang Gao & Yuen Lam Dora Ng & Valeriia Sapozhnikova & Philipp Mertins & Jan Krönke & Alexander Dömling, 2023. "Direct-to-biology, automated, nano-scale synthesis, and phenotypic screening-enabled E3 ligase modulator discovery," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    13. Lucien F. Krapp & Luciano A. Abriata & Fabio Cortés Rodriguez & Matteo Dal Peraro, 2023. "PeSTo: parameter-free geometric deep learning for accurate prediction of protein binding interfaces," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    14. Meropi Bagka & Hyeonyi Choi & Margaux Héritier & Hanna Schwaemmle & Quentin T. L. Pasquer & Simon M. G. Braun & Leonardo Scapozza & Yibo Wu & Sascha Hoogendoorn, 2023. "Targeted protein degradation reveals BET bromodomains as the cellular target of Hedgehog pathway inhibitor-1," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    15. Seref Gul & Yasemin Kubra Akyel & Zeynep Melis Gul & Safak Isin & Onur Ozcan & Tuba Korkmaz & Saba Selvi & Ibrahim Danis & Ozgecan Savlug Ipek & Fatih Aygenli & Ali Cihan Taskin & Büşra Aytül Akarlar , 2022. "Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice," Nature Communications, Nature, vol. 13(1), pages 1-17, 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_s41467-024-50642-0. 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.