Design of protein-binding proteins from the target structure alone

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, Scott Thomas Russell Walsh, Nathaniel Bennett, Ashish Phal, Aerin Yang, Lisa Kozodoy, Michelle DeWitt, Lora Picton, Lauren Miller, Eva-Maria Strauch, Nicholas D. DeBouver, Allison Pires, Asim K. Bera, Samer Halabiya, Bradley Hammerson, Wei Yang, Steffen Bernard, Lance Stewart, Ian A. Wilson, Hannele Ruohola-Baker, Joseph Schlessinger, Sangwon Lee, Savvas N. Savvides, K. Christopher Garcia and David Baker ()
Additional contact information
Longxing Cao: University of Washington
Brian Coventry: University of Washington
Inna Goreshnik: University of Washington
Buwei Huang: University of Washington
William Sheffler: University of Washington
Joon Sung Park: Yale University School of Medicine
Kevin M. Jude: Stanford University School of Medicine
Iva Marković: VIB-UGent Center for Inflammation Research
Rameshwar U. Kadam: The Scripps Research Institute
Koen H. G. Verschueren: VIB-UGent Center for Inflammation Research
Kenneth Verstraete: VIB-UGent Center for Inflammation Research
Scott Thomas Russell Walsh: National Cancer Institute, National Institutes of Health
Nathaniel Bennett: University of Washington
Ashish Phal: University of Washington
Aerin Yang: Stanford University School of Medicine
Lisa Kozodoy: University of Washington
Michelle DeWitt: University of Washington
Lora Picton: Stanford University School of Medicine
Lauren Miller: University of Washington
Eva-Maria Strauch: University of Georgia
Nicholas D. DeBouver: UCB Pharma
Allison Pires: Seattle Structural Genomics Center for Infectious Disease (SSGCID)
Asim K. Bera: University of Washington
Samer Halabiya: University of Washington
Bradley Hammerson: Seattle Structural Genomics Center for Infectious Disease (SSGCID)
Wei Yang: University of Washington
Steffen Bernard: The Scripps Research Institute
Lance Stewart: University of Washington
Ian A. Wilson: The Scripps Research Institute
Hannele Ruohola-Baker: 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
K. Christopher Garcia: Stanford University School of Medicine
David Baker: University of Washington

Nature, 2022, vol. 605, issue 7910, 551-560

Abstract: 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.

Date: 2022
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Citations: View citations in EconPapers (12)

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DOI: 10.1038/s41586-022-04654-9

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