De novo design of immunoglobulin-like domains.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
03 10 2022
03 10 2022
Historique:
received:
24
03
2022
accepted:
17
08
2022
entrez:
3
10
2022
pubmed:
4
10
2022
medline:
6
10
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36192397
doi: 10.1038/s41467-022-33004-6
pii: 10.1038/s41467-022-33004-6
pmc: PMC9530121
doi:
Substances chimiques
Antibodies
0
Complementarity Determining Regions
0
Single-Domain Antibodies
0
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5661Subventions
Organisme : Howard Hughes Medical Institute
Pays : United States
Informations de copyright
© 2022. The Author(s).
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