7T84

Structure of angiotensin II type I receptor (AT1R) nanobody antagonist AT118i4h32 G26D T57I variant

Summary for 7T84

• Entry DOI: 10.2210/pdb7t84/pdb
• Descriptor: Nanobody AT118i4h32 G26D T57I, CITRIC ACID, GLYCEROL, ... (6 entities in total)
• Functional Keywords: single chain antibody fragment, immune system
• Biological source: synthetic construct
• Total number of polymer chains: 8
• Total formula weight: 116568.55

Authors

Nemeth, G.R.,Skiba, M.A.,Kruse, A.C. (deposition date: 2021-12-15, release date: 2022-12-07, Last modification date: 2024-10-16)

Primary citation

Harvey, E.P.,Shin, J.E.,Skiba, M.A.,Nemeth, G.R.,Hurley, J.D.,Wellner, A.,Shaw, A.Y.,Miranda, V.G.,Min, J.K.,Liu, C.C.,Marks, D.S.,Kruse, A.C.
An in silico method to assess antibody fragment polyreactivity.
Nat Commun, 13:7554-7554, 2022

PubMed Abstract: Antibodies are essential biological research tools and important therapeutic agents, but some exhibit non-specific binding to off-target proteins and other biomolecules. Such polyreactive antibodies compromise screening pipelines, lead to incorrect and irreproducible experimental results, and are generally intractable for clinical development. Here, we design a set of experiments using a diverse naïve synthetic camelid antibody fragment (nanobody) library to enable machine learning models to accurately assess polyreactivity from protein sequence (AUC > 0.8). Moreover, our models provide quantitative scoring metrics that predict the effect of amino acid substitutions on polyreactivity. We experimentally test our models' performance on three independent nanobody scaffolds, where over 90% of predicted substitutions successfully reduced polyreactivity. Importantly, the models allow us to diminish the polyreactivity of an angiotensin II type I receptor antagonist nanobody, without compromising its functional properties. We provide a companion web-server that offers a straightforward means of predicting polyreactivity and polyreactivity-reducing mutations for any given nanobody sequence.

PubMed: 36477674
DOI: 10.1038/s41467-022-35276-4

Experimental method

X-RAY DIFFRACTION (1.6 Å)