5HHV

Inhibiting complex IL-17A and IL-17RA interactions with a linear peptide

Summary for 5HHV

• Entry DOI: 10.2210/pdb5hhv/pdb
• Related: 5HHX 5HI3 5HI4 5HI5
• Descriptor: Interleukin-17A, CAT-2000 FAB heavy chain, IL-17A peptide inhibitor, ... (5 entities in total)
• Functional Keywords: il-17, inflammation, inhibitor, complex crystal structure, immune system-inhibitor complex, immune system/inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Secreted: Q16552
• Total number of polymer chains: 5
• Total formula weight: 78381.25

Authors

Liu, S. (deposition date: 2016-01-11, release date: 2016-06-01, Last modification date: 2024-11-20)

Primary citation

Liu, S.,Desharnais, J.,Sahasrabudhe, P.V.,Jin, P.,Li, W.,Oates, B.D.,Shanker, S.,Banker, M.E.,Chrunyk, B.A.,Song, X.,Feng, X.,Griffor, M.,Jimenez, J.,Chen, G.,Tumelty, D.,Bhat, A.,Bradshaw, C.W.,Woodnutt, G.,Lappe, R.W.,Thorarensen, A.,Qiu, X.,Withka, J.M.,Wood, L.D.
Inhibiting complex IL-17A and IL-17RA interactions with a linear peptide.
Sci Rep, 6:26071-26071, 2016

PubMed Abstract: IL-17A is a pro-inflammatory cytokine that has been implicated in autoimmune and inflammatory diseases. Monoclonal antibodies inhibiting IL-17A signaling have demonstrated remarkable efficacy, but an oral therapy is still lacking. A high affinity IL-17A peptide antagonist (HAP) of 15 residues was identified through phage-display screening followed by saturation mutagenesis optimization and amino acid substitutions. HAP binds specifically to IL-17A and inhibits the interaction of the cytokine with its receptor, IL-17RA. Tested in primary human cells, HAP blocked the production of multiple inflammatory cytokines. Crystal structure studies revealed that two HAP molecules bind to one IL-17A dimer symmetrically. The N-terminal portions of HAP form a β-strand that inserts between two IL-17A monomers while the C-terminal section forms an α helix that directly blocks IL-17RA from binding to the same region of IL-17A. This mode of inhibition suggests opportunities for developing peptide antagonists against this challenging target.

PubMed: 27184415
DOI: 10.1038/srep26071

Experimental method

X-RAY DIFFRACTION (2.2 Å)