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Subunit disassembly and inhibition of TNFα by a semi-synthetic bicyclic peptide.

Luzi S, Kondo Y, Bernard E, Stadler LK, Vaysburd M, Winter G, Holliger P - Protein Eng. Des. Sel. (2015)

Bottom Line: Macrocyclic peptides are potentially a source of powerful drugs, but their de novo discovery remains challenging.The bicyclic peptide M21 (ACPPCLWQVLC) comprises two loops covalently anchored to a 2,4,6-trimethyl-mesitylene core and upon binding induces disassembly of the trimeric TNFα cytokine into dimers and monomers.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.

View Article: PubMed Central - PubMed

Affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.

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M21-TNF complex structure. (A) M21 bicyclic peptide (grey) is shown bound at the interface between 2 TNFα subunits A, B (yellow, blue) (B) as a stick diagram with elemental colours C (grey), N (blue), S (orange) and O (red).
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GZU055F5: M21-TNF complex structure. (A) M21 bicyclic peptide (grey) is shown bound at the interface between 2 TNFα subunits A, B (yellow, blue) (B) as a stick diagram with elemental colours C (grey), N (blue), S (orange) and O (red).

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.


Subunit disassembly and inhibition of TNFα by a semi-synthetic bicyclic peptide.

Luzi S, Kondo Y, Bernard E, Stadler LK, Vaysburd M, Winter G, Holliger P - Protein Eng. Des. Sel. (2015)

M21-TNF complex structure. (A) M21 bicyclic peptide (grey) is shown bound at the interface between 2 TNFα subunits A, B (yellow, blue) (B) as a stick diagram with elemental colours C (grey), N (blue), S (orange) and O (red).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4378371&req=5

GZU055F5: M21-TNF complex structure. (A) M21 bicyclic peptide (grey) is shown bound at the interface between 2 TNFα subunits A, B (yellow, blue) (B) as a stick diagram with elemental colours C (grey), N (blue), S (orange) and O (red).
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.

Bottom Line: Macrocyclic peptides are potentially a source of powerful drugs, but their de novo discovery remains challenging.The bicyclic peptide M21 (ACPPCLWQVLC) comprises two loops covalently anchored to a 2,4,6-trimethyl-mesitylene core and upon binding induces disassembly of the trimeric TNFα cytokine into dimers and monomers.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.

View Article: PubMed Central - PubMed

Affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.

Show MeSH
Related in: MedlinePlus