De novo design of immunoglobulin-like domains

October 17, 2022


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 & Enrique Marcos




Nature Communications


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.


J series


antibody, nanobodies, immunoglobulin-like domains