9F90

Crystal structure of a designed three-motif Respiratory Syncytial Virus immunogen in complex with motavizumab fab

Summary for 9F90

• Entry DOI: 10.2210/pdb9f90/pdb
• Descriptor: Motavizumab Fab light chain, Motavizumab Fab heavy chain, RSVF-multi-epitope designed scaffold, ... (5 entities in total)
• Functional Keywords: designed immunogen, specific binding, rsv f protein, de novo protein
• Biological source: Mus musculus; More
• Total number of polymer chains: 6
• Total formula weight: 126688.66

Authors

Castro, K.M.,Correia, B.E. (deposition date: 2024-05-07, release date: 2025-05-21, Last modification date: 2025-12-17)

Primary citation

Castro, K.M.,Watson, J.L.,Wang, J.,Southern, J.,Ayardulabi, R.,Georgeon, S.,Rosset, S.,Baker, D.,Correia, B.E.
Accurate single-domain scaffolding of three nonoverlapping protein epitopes using deep learning.
Nat.Chem.Biol., 2025

PubMed Abstract: De novo protein design has seen major success in scaffolding single functional motifs; however, in nature, most proteins present multiple functional sites. Here, we describe an approach to simultaneously scaffold multiple functional sites in a single-domain protein using deep learning. We designed small single-domain immunogens, under 130 residues, that present three distinct and irregular motifs from respiratory syncytial virus. These motifs together comprise nearly half of the designed proteins; hence, the overall folds are quite unusual with little global similarity to proteins in the Protein Data Bank. Despite this, X-ray crystal structures confirmed the accuracy of presentation of each of the motifs and the multiepitope design yields improved cross-reactive titers and neutralizing response compared to a single-epitope immunogen. The successful presentation of three distinct binding surfaces in a small single-domain protein highlights the power of generative deep learning methods to solve complex protein design problems.

PubMed: 41350440
DOI: 10.1038/s41589-025-02083-z

Experimental method

X-RAY DIFFRACTION (2.91 Å)