9DXX

Crystal structure of the A/Puerto Rico/8/1934 (H1N1) influenza virus hemagglutinin in complex with D-peptide

Summary for 9DXX

• Entry DOI: 10.2210/pdb9dxx/pdb
• Descriptor: Hemagglutinin HA1 chain, Hemagglutinin HA2 chain, D-peptide, ... (9 entities in total)
• Functional Keywords: hemagglutinin, d-peptide, viral protein
• Biological source: Influenza A virus (A/Puerto Rico/8/1934(H1N1)); More
• Total number of polymer chains: 3
• Total formula weight: 62884.35

Authors

Kadam, R.U.,Wilson, I.A. (deposition date: 2024-10-12, release date: 2025-06-25, Last modification date: 2025-07-30)

Primary citation

Juraszek, J.,Kadam, R.U.,Branduardi, D.,van Ameijde, J.,Garg, D.,Dailly, N.,Jongeneelen, M.,Vermond, J.,Brakenhoff, J.P.J.,Brandenburg, B.,van Dongen, M.J.P.,Vogels, R.,Friesen, R.H.E.,Wilson, I.A.
De novo design of D-peptide ligands: Application to influenza virus hemagglutinin.
Proc.Natl.Acad.Sci.USA, 122:e2426554122-e2426554122, 2025

PubMed Abstract: D-peptides hold great promise as therapeutics by alleviating the challenges of metabolic stability and immunogenicity in L-peptides. However, current D-peptide discovery methods are severely limited by specific size, structure, and the chemical synthesizability of their protein targets. Here, we describe a computational method for de novo design of D-peptides that bind to an epitope of interest on the target protein using Rosetta's hotspot-centric approach. The approach comprises identifying hotspot sidechains in a functional protein-protein interaction and grafting these side chains onto much smaller structured peptide scaffolds of opposite chirality. The approach enables more facile design of D-peptides and its applicability is demonstrated by design of D-peptidic binders of influenza A virus hemagglutinin, resulting in identification of multiple D-peptide lead series. The X-ray structure of one of the leads at 2.38 Å resolution verifies the validity of the approach. This method should be generally applicable to targets with detailed structural information, independent of molecular size, and accelerate development of stable, peptide-based therapeutics.

PubMed: 40577121
DOI: 10.1073/pnas.2426554122

Experimental method

X-RAY DIFFRACTION (2.37 Å)