8XYR

De novo designed protein GPX4-2

Summary for 8XYR

• Entry DOI: 10.2210/pdb8xyr/pdb
• Descriptor: De novo designed GPX4-2 (2 entities in total)
• Functional Keywords: de novo protein
• Biological source: synthetic construct
• Total number of polymer chains: 1
• Total formula weight: 20227.24

Authors

Liu, L.J.,Guo, Z.,Lai, L.H. (deposition date: 2024-01-20, release date: 2024-10-02)

Primary citation

Liu, J.,Guo, Z.,You, H.,Zhang, C.,Lai, L.
All-Atom Protein Sequence Design Based on Geometric Deep Learning.
Angew.Chem.Int.Ed.Engl., :e202411461-e202411461, 2024

PubMed Abstract: Designing sequences for specific protein backbones is a key step in creating new functional proteins. Here, we introduce GeoSeqBuilder, a deep learning framework that integrates protein sequence generation with side chain conformation prediction to produce the complete all-atom structures for designed sequences. GeoSeqBuilder uses spatial geometric features from protein backbones and explicitly includes three-body interactions of neighboring residues. GeoSeqBuilder achieves native residue type recovery rate of 51.6%, comparable to ProteinMPNN and  other leading methods, while accurately predicting side chain conformations. We first used GeoSeqBuilder to design sequences for thioredoxin and a hallucinated three-helical bundle protein. All the 15 tested sequences expressed as soluble monomeric proteins with high thermal stability, and the 2 high-resolution crystal structures solved closely match the designed models. The generated protein sequences exhibit low similarity (minimum 23%) to the original sequences, with significantly altered hydrophobic cores. We further redesigned the hydrophobic core of glutathione peroxidase 4, and 3 of the 5 designs showed improved enzyme activity. Although further testing is needed, the high experimental success rate in our testing demonstrates that GeoSeqBuilder is a powerful tool for designing novel sequences for predefined protein structures with atomic details. GeoSeqBuilder is available at https://github.com/PKUliujl/GeoSeqBuilder.

PubMed: 39295564
DOI: 10.1002/anie.202411461

Experimental method

X-RAY DIFFRACTION (1.87 Å)