9YIC

Crystal structure of human IL-17A in complex with Compound 1

This is a non-PDB format compatible entry.

Summary for 9YIC

• Entry DOI: 10.2210/pdb9yic/pdb
• Descriptor: Interleukin-17A, (3S)-N-[(3-{[(1S)-2-anilino-1-cyclohexyl-2-oxoethyl]carbamoyl}phenyl)methyl]-2,2-dimethylthiomorpholine-3-carboxamide (3 entities in total)
• Functional Keywords: dimer, cysteine-knot, cytokine
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 57885.18

Authors

Armstrong, A.A.,Milligan, C.M.,Luo, J. (deposition date: 2025-10-01, release date: 2025-10-15, Last modification date: 2025-12-03)

Primary citation

Milla, M.E.,Blevitt, J.M.,Goldberg, S.D.,Armstrong, A.A.,Blain, K.Y.,Herman, K.L.,Liu, A.X.,Luna, R.,Milligan, C.M.,Patrick, A.N.,Steele, R.A.,Bembenek, S.D.,Centrella, P.,Clark, M.A.,Cuozzo, J.W.,Disch, J.S.,Domingo, D.,Hunt, A.,Hupp, C.D.,Keefe, A.D.,Luo, J.,Mirzadegan, T.,Nelen, M.I.,Resnicow, D.I.,Sigel, E.A.,Soutter, H.H.,Troast, D.M.,Xue, X.,Yi, F.,Zhang, Y.,Jackson, P.F.,Edwards, J.P.,Lumb, K.J.
A Novel Small Molecule Allosteric Inhibitor of IL-17A from a DNA-Encoded Library.
Acs Med.Chem.Lett., 16:2301-2308, 2025

PubMed Abstract: A novel series of inhibitors of the interaction of IL-17A with its cognate receptor has been discovered using DNA-encoded library (DEL) technology. The lead compound (JNJ627, Compound ) of the series occupies the interior interface of the IL-17A homodimer and disables receptor binding. The mechanism of action involves allosteric disruption of the IL-17A quaternary structure to prevent adoption of the receptor-binding conformation, rather than direct orthosteric inhibition at the receptor-binding site. Molecules of this series exhibit remarkably slow on-rate kinetics and potent inhibition of IL-17A signaling in human primary cells.

PubMed: 41256970
DOI: 10.1021/acsmedchemlett.5c00502

Experimental method

X-RAY DIFFRACTION (3.15 Å)