8TUD

IgG1 Fc Heterodimer combYSelect2

Summary for 8TUD

• Entry DOI: 10.2210/pdb8tud/pdb
• Descriptor: Immunoglobulin gamma-1 heavy chain, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: igg1 fc, heterodimer, immune system
• Biological source: Homo sapiens x Mus musculus hybrid cell line; More
• Total number of polymer chains: 2
• Total formula weight: 55205.82

Authors

Azzam, T.,Du, J.J.,Sundberg, E.J. (deposition date: 2023-08-16, release date: 2024-06-26, Last modification date: 2024-10-23)

Primary citation

Azzam, T.,Du, J.J.,Flowers, M.W.,Ali, A.V.,Hunn, J.C.,Vijayvargiya, N.,Knagaram, R.,Bogacz, M.,Maravillas, K.E.,Sastre, D.E.,Fields, J.K.,Mirzaei, A.,Pierce, B.G.,Sundberg, E.J.
Combinatorially restricted computational design of protein-protein interfaces to produce IgG heterodimers.
Sci Adv, 10:eadk8157-eadk8157, 2024

PubMed Abstract: Redesigning protein-protein interfaces is an important tool for developing therapeutic strategies. Interfaces can be redesigned by in silico screening, which allows for efficient sampling of a large protein space before experimental validation. However, computational costs limit the number of combinations that can be reasonably sampled. Here, we present combinatorial tyrosine (Y)/serine (S) selection (combYSelect), a computational approach combining in silico determination of the change in binding free energy (ΔΔ) of an interface with a highly restricted library composed of just two amino acids, tyrosine and serine. We used combYSelect to design two immunoglobulin G (IgG) heterodimers-combYSelect1 (L368S/D399Y-K409S/T411Y) and combYSelect2 (D399Y/K447S-K409S/T411Y)-that exhibit near-optimal heterodimerization, without affecting IgG stability or function. We solved the crystal structures of these heterodimers and found that dynamic π-stacking interactions and polar contacts drive preferential heterodimeric interactions. Finally, we demonstrated the utility of our combYSelect heterodimers by engineering both a bispecific antibody and a cytokine trap for two unique therapeutic applications.

PubMed: 38598628
DOI: 10.1126/sciadv.adk8157

Experimental method

X-RAY DIFFRACTION (3 Å)