Rationally seeded computational protein design of ɑ-helical barrels.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
20 Jun 2024
20 Jun 2024
Historique:
received:
25
08
2023
accepted:
09
05
2024
medline:
21
6
2024
pubmed:
21
6
2024
entrez:
20
6
2024
Statut:
aheadofprint
Résumé
Computational protein design is advancing rapidly. Here we describe efficient routes starting from validated parallel and antiparallel peptide assemblies to design two families of α-helical barrel proteins with central channels that bind small molecules. Computational designs are seeded by the sequences and structures of defined de novo oligomeric barrel-forming peptides, and adjacent helices are connected by loop building. For targets with antiparallel helices, short loops are sufficient. However, targets with parallel helices require longer connectors; namely, an outer layer of helix-turn-helix-turn-helix motifs that are packed onto the barrels. Throughout these computational pipelines, residues that define open states of the barrels are maintained. This minimizes sequence sampling, accelerating the design process. For each of six targets, just two to six synthetic genes are made for expression in Escherichia coli. On average, 70% of these genes express to give soluble monomeric proteins that are fully characterized, including high-resolution structures for most targets that match the design models with high accuracy.
Identifiants
pubmed: 38902458
doi: 10.1038/s41589-024-01642-0
pii: 10.1038/s41589-024-01642-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)
ID : BB/V004220/1
Organisme : RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)
ID : BB/S002820/1
Organisme : RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)
ID : BB/V004220/1
Organisme : RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)
ID : BB/S002820/1
Organisme : RCUK | Engineering and Physical Sciences Research Council (EPSRC)
ID : EP/T012455/1
Organisme : RCUK | Engineering and Physical Sciences Research Council (EPSRC)
ID : EP/T012455/1
Organisme : RCUK | Engineering and Physical Sciences Research Council (EPSRC)
ID : EP/T012455/1
Informations de copyright
© 2024. The Author(s).
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