Subunit disassembly and inhibition of TNFα by a semi-synthetic bicyclic peptide.
Bottom Line: Macrocyclic peptides are potentially a source of powerful drugs, but their de novo discovery remains challenging.A 2.9 Å crystal structure of the M21/hTNFα complex reveals the peptide bound to a hTNFα dimer at a normally buried epitope in the trimer interface overlapping the binding site of a previously discovered small molecule ligand (SPD304), which also induces TNF trimer dissociation and synergizes with M21 in the inhibition of TNFα cytotoxicity.The discovery of M21 underlines the potential of semi-synthetic bicyclic peptides as ligands for the discovery of cryptic epitopes, some of which are poorly accessible to antibodies.
Affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.Show MeSH
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Mentions: The asymmetric unit of the crystal consists of 2 copies of a TNFα—M21 bicycle complex at a ratio of 2 : 1. The structure shows the M21 peptide bound to a dimer of TNFα subunits (A and B) (Fig. 5A and B) interacting with residues from both A and B and with an average interface area of TNFα and M21 of 231 Å2 (compared to 398 Å2 for the TNFα subunit interface).Fig. 5.
Affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.