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
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Citations
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Cited by:
- 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.
- 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.
- 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.
- 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.
- 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).
- 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.
- 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.
- 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.
- 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.
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