De novo design of immunoglobulin-like domains

Tamuka M. Chidyausiku, Soraia R. Mendes, Jason C. Klima, Marta Nadal, Ulrich Eckhard, Jorge Roel-Touris, Scott Houliston, Tibisay Guevara, Hugh K. Haddox, Adam Moyer, Cheryl H. Arrowsmith, F. Xavier Gomis-Rüth (), David Baker () and Enrique Marcos ()
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Tamuka M. Chidyausiku: University of Washington
Soraia R. Mendes: Molecular Biology Institute of Barcelona (IBMB-CSIC)
Jason C. Klima: University of Washington
Marta Nadal: Molecular Biology Institute of Barcelona (IBMB-CSIC)
Ulrich Eckhard: Molecular Biology Institute of Barcelona (IBMB-CSIC)
Jorge Roel-Touris: Molecular Biology Institute of Barcelona (IBMB-CSIC)
Scott Houliston: University of Toronto
Tibisay Guevara: Molecular Biology Institute of Barcelona (IBMB-CSIC)
Hugh K. Haddox: University of Washington
Adam Moyer: University of Washington
Cheryl H. Arrowsmith: University of Toronto
F. Xavier Gomis-Rüth: Molecular Biology Institute of Barcelona (IBMB-CSIC)
David Baker: University of Washington
Enrique Marcos: Molecular Biology Institute of Barcelona (IBMB-CSIC)

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Antibodies, and antibody derivatives such as nanobodies, contain immunoglobulin-like (Ig) β-sandwich scaffolds which anchor the hypervariable antigen-binding loops and constitute the largest growing class of drugs. Current engineering strategies for this class of compounds rely on naturally existing Ig frameworks, which can be hard to modify and have limitations in manufacturability, designability and range of action. Here, we develop design rules for the central feature of the Ig fold architecture—the non-local cross-β structure connecting the two β-sheets—and use these to design highly stable Ig domains de novo, confirm their structures through X-ray crystallography, and show they can correctly scaffold functional loops. Our approach opens the door to the design of antibody-like scaffolds with tailored structures and superior biophysical properties.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33004-6

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DOI: 10.1038/s41467-022-33004-6

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