IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v605y2022i7910d10.1038_s41586-022-04654-9.html
   My bibliography  Save this article

Design of protein-binding proteins from the target structure alone

Author

Listed:
  • Longxing Cao

    (University of Washington
    University of Washington)

  • Brian Coventry

    (University of Washington
    University of Washington
    University of Washington)

  • Inna Goreshnik

    (University of Washington
    University of Washington)

  • Buwei Huang

    (University of Washington
    University of Washington
    University of Washington)

  • William Sheffler

    (University of Washington
    University of Washington)

  • Joon Sung Park

    (Yale University School of Medicine)

  • Kevin M. Jude

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Iva Marković

    (VIB-UGent Center for Inflammation Research
    Ghent University)

  • Rameshwar U. Kadam

    (The Scripps Research Institute)

  • Koen H. G. Verschueren

    (VIB-UGent Center for Inflammation Research
    Ghent University)

  • Kenneth Verstraete

    (VIB-UGent Center for Inflammation Research
    Ghent University)

  • Scott Thomas Russell Walsh

    (National Cancer Institute, National Institutes of Health
    J.A.M.E.S. Farm)

  • Nathaniel Bennett

    (University of Washington
    University of Washington
    University of Washington)

  • Ashish Phal

    (University of Washington
    University of Washington
    University of Washington)

  • Aerin Yang

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Lisa Kozodoy

    (University of Washington
    University of Washington)

  • Michelle DeWitt

    (University of Washington
    University of Washington)

  • Lora Picton

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Lauren Miller

    (University of Washington
    University of Washington)

  • Eva-Maria Strauch

    (University of Georgia)

  • Nicholas D. DeBouver

    (UCB Pharma
    Seattle Structural Genomics Center for Infectious Disease (SSGCID))

  • Allison Pires

    (Seattle Structural Genomics Center for Infectious Disease (SSGCID)
    Seattle Children’s Center for Global Infectious Disease Research)

  • Asim K. Bera

    (University of Washington
    University of Washington)

  • Samer Halabiya

    (University of Washington)

  • Bradley Hammerson

    (Seattle Structural Genomics Center for Infectious Disease (SSGCID))

  • Wei Yang

    (University of Washington
    University of Washington)

  • Steffen Bernard

    (The Scripps Research Institute)

  • Lance Stewart

    (University of Washington
    University of Washington)

  • Ian A. Wilson

    (The Scripps Research Institute
    The Scripps Research Institute)

  • Hannele Ruohola-Baker

    (University of Washington
    University of Washington)

  • Joseph Schlessinger

    (Yale University School of Medicine)

  • Sangwon Lee

    (Yale University School of Medicine)

  • Savvas N. Savvides

    (VIB-UGent Center for Inflammation Research
    Ghent University)

  • K. Christopher Garcia

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • David Baker

    (University of Washington
    University of Washington
    University of Washington)

Abstract

The design of proteins that bind to a specific site on the surface of a target protein using no information other than the three-dimensional structure of the target remains a challenge1–5. Here we describe a general solution to this problem that starts with a broad exploration of the vast space of possible binding modes to a selected region of a protein surface, and then intensifies the search in the vicinity of the most promising binding modes. We demonstrate the broad applicability of this approach through the de novo design of binding proteins to 12 diverse protein targets with different shapes and surface properties. Biophysical characterization shows that the binders, which are all smaller than 65 amino acids, are hyperstable and, following experimental optimization, bind their targets with nanomolar to picomolar affinities. We succeeded in solving crystal structures of five of the binder–target complexes, and all five closely match the corresponding computational design models. Experimental data on nearly half a million computational designs and hundreds of thousands of point mutants provide detailed feedback on the strengths and limitations of the method and of our current understanding of protein–protein interactions, and should guide improvements of both. Our approach enables the targeted design of binders to sites of interest on a wide variety of proteins for therapeutic and diagnostic applications.

Suggested Citation

  • Longxing Cao & Brian Coventry & Inna Goreshnik & Buwei Huang & William Sheffler & Joon Sung Park & Kevin M. Jude & Iva Marković & Rameshwar U. Kadam & Koen H. G. Verschueren & Kenneth Verstraete & Sco, 2022. "Design of protein-binding proteins from the target structure alone," Nature, Nature, vol. 605(7910), pages 551-560, May.
  • Handle: RePEc:nat:nature:v:605:y:2022:i:7910:d:10.1038_s41586-022-04654-9
    DOI: 10.1038/s41586-022-04654-9
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-022-04654-9
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/s41586-022-04654-9?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
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Claudia L. Driscoll & Anthony H. Keeble & Mark R. Howarth, 2024. "SpyMask enables combinatorial assembly of bispecific binders," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Xinchen Lv & Yuanyuan Zhang & Ke Sun & Qi Yang & Jianhua Luo & Liang Tao & Peilong Lu, 2024. "De novo design of mini-protein binders broadly neutralizing Clostridioides difficile toxin B variants," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Betz, Ulrich A.K. & Arora, Loukik & Assal, Reem A. & Azevedo, Hatylas & Baldwin, Jeremy & Becker, Michael S. & Bostock, Stefan & Cheng, Vinton & Egle, Tobias & Ferrari, Nicola & Schneider-Futschik, El, 2023. "Game changers in science and technology - now and beyond," Technological Forecasting and Social Change, Elsevier, vol. 193(C).
    4. Qishan Liang & Tao Yu & Eric Kofman & Pratibha Jagannatha & Kevin Rhine & Brian A. Yee & Kevin D. Corbett & Gene W. Yeo, 2024. "High-sensitivity in situ capture of endogenous RNA-protein interactions in fixed cells and primary tissues," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Thomas W. Linsky & Kyle Noble & Autumn R. Tobin & Rachel Crow & Lauren Carter & Jeffrey L. Urbauer & David Baker & Eva-Maria Strauch, 2022. "Sampling of structure and sequence space of small protein folds," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    6. Edward P. Harvey & Jung-Eun Shin & Meredith A. Skiba & Genevieve R. Nemeth & Joseph D. Hurley & Alon Wellner & Ada Y. Shaw & Victor G. Miranda & Joseph K. Min & Chang C. Liu & Debora S. Marks & Andrew, 2022. "An in silico method to assess antibody fragment polyreactivity," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    7. Sasha B. Ebrahimi & Devleena Samanta, 2023. "Engineering protein-based therapeutics through structural and chemical design," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    8. Ai Vu Hong & Laurence Suel & Eva Petat & Auriane Dubois & Pierre-Romain Le Brun & Nicolas Guerchet & Philippe Veron & Jérôme Poupiot & Isabelle Richard, 2024. "An engineered AAV targeting integrin alpha V beta 6 presents improved myotropism across species," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    9. Buwei Huang & Brian Coventry & Marta T. Borowska & Dimitrios C. Arhontoulis & Marc Exposit & Mohamad Abedi & Kevin M. Jude & Samer F. Halabiya & Aza Allen & Cami Cordray & Inna Goreshnik & Maggie Ahlr, 2024. "De novo design of miniprotein antagonists of cytokine storm inducers," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    10. Nathaniel R. Bennett & Brian Coventry & Inna Goreshnik & Buwei Huang & Aza Allen & Dionne Vafeados & Ying Po Peng & Justas Dauparas & Minkyung Baek & Lance Stewart & Frank DiMaio & Steven Munck & Savv, 2023. "Improving de novo protein binder design with deep learning," Nature Communications, Nature, vol. 14(1), pages 1-9, 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:nature:v:605:y:2022:i:7910:d:10.1038_s41586-022-04654-9. 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.

    We have no bibliographic references for this item. You can help adding them by using 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.