A glutamine-based single α-helix scaffold to target globular proteins

Albert Escobedo (), Jonathan Piccirillo, Juan Aranda, Tammo Diercks, Borja Mateos, Carla Garcia-Cabau, Macarena Sánchez-Navarro, Busra Topal, Mateusz Biesaga, Lasse Staby, Birthe B. Kragelund, Jesús García, Oscar Millet, Modesto Orozco, Murray Coles, Ramon Crehuet and Xavier Salvatella ()
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Albert Escobedo: The Barcelona Institute of Science and Technology
Jonathan Piccirillo: The Barcelona Institute of Science and Technology
Juan Aranda: The Barcelona Institute of Science and Technology
Tammo Diercks: Bizkaia Science and Technology Park
Borja Mateos: The Barcelona Institute of Science and Technology
Carla Garcia-Cabau: The Barcelona Institute of Science and Technology
Macarena Sánchez-Navarro: Instituto de Parasitología y Biomedicina López Neyra (IPBLN-CSIC)
Busra Topal: The Barcelona Institute of Science and Technology
Mateusz Biesaga: The Barcelona Institute of Science and Technology
Lasse Staby: University of Copenhagen
Birthe B. Kragelund: University of Copenhagen
Jesús García: The Barcelona Institute of Science and Technology
Oscar Millet: Bizkaia Science and Technology Park
Modesto Orozco: The Barcelona Institute of Science and Technology
Murray Coles: Max Planck Institute for Biology
Ramon Crehuet: CSIC
Xavier Salvatella: The Barcelona Institute of Science and Technology

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract The binding of intrinsically disordered proteins to globular ones can require the folding of motifs into α-helices. These interactions offer opportunities for therapeutic intervention but their modulation with small molecules is challenging because they bury large surfaces. Linear peptides that display the residues that are key for binding can be targeted to globular proteins when they form stable helices, which in most cases requires their chemical modification. Here we present rules to design peptides that fold into single α-helices by instead concatenating glutamine side chain to main chain hydrogen bonds recently discovered in polyglutamine helices. The resulting peptides are uncharged, contain only natural amino acids, and their sequences can be optimized to interact with specific targets. Our results provide design rules to obtain single α-helices for a wide range of applications in protein engineering and drug design.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34793-6

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DOI: 10.1038/s41467-022-34793-6

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