6P9E

Crystal structure of IL-36gamma complexed to A-552

6P9E の概要

• エントリーDOI: 10.2210/pdb6p9e/pdb
• 分子名称: Interleukin-36 gamma, (2S)-2-{[4-(3-amino-4-methylphenyl)-6-methylpyrimidin-2-yl]oxy}-3-methoxy-3,3-diphenylpropanoic acid (3 entities in total)
• 機能のキーワード: il-36, small molecule antagonist, cytokine
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 17514.95

構造登録者

Argiriadi, M.A.,Todorovic, T.,Su, Z.,Putman, B.,Kakavas, S.J.,Salte, K.M.,McDonald, H.A.,Wetter, J.B.,Paulsboe, S.E.,Sun, Q.,Gerstein, C.E.,Medina, L.,Sielaff, B.,Sadhukhan, R.,Stockmann, H.,Richardson, P.L.,Qiu, W.,Henry, R.F.,Herold, J.M.,Shotwell, J.B.,McGaraughty, S.P.,Honore, P.,Gopalakrishnan, S.M.,Sun, C.C.,Scott, V.E. (登録日: 2019-06-10, 公開日: 2019-06-26, 最終更新日: 2023-10-11)

主引用文献

Todorovic, V.,Su, Z.,Putman, C.B.,Kakavas, S.J.,Salte, K.M.,McDonald, H.A.,Wetter, J.B.,Paulsboe, S.E.,Sun, Q.,Gerstein, C.E.,Medina, L.,Sielaff, B.,Sadhukhan, R.,Stockmann, H.,Richardson, P.L.,Qiu, W.,Argiriadi, M.A.,Henry, R.F.,Herold, J.M.,Shotwell, J.B.,McGaraughty, S.P.,Honore, P.,Gopalakrishnan, S.M.,Sun, C.C.,Scott, V.E.
Small Molecule IL-36 gamma Antagonist as a Novel Therapeutic Approach for Plaque Psoriasis.
Sci Rep, 9:9089-9089, 2019

PubMed Abstract: IL-36 cytokines are pro-inflammatory members of the IL-1 family that are upregulated in inflammatory disorders. Specifically, IL-36γ is highly expressed in active psoriatic lesions and can drive pro-inflammatory processes in 3D human skin equivalents supporting a role for this target in skin inflammation. Small molecule antagonists of interleukins have been historically challenging to generate. Nevertheless, we performed a small molecule high-throughput screen to identify IL-36 antagonists using a novel TR-FRET binding assay. Several compounds, including 2-oxypyrimidine containing structural analogs of the marketed endothelin receptor A antagonist Ambrisentan, were identified as hits from the screen. A-552 was identified as a the most potent antagonist of human IL-36γ, but not the closely related family member IL-36α, was capable of attenuating IL-36γ induced responses in mouse and human disease models. Additionally, x-ray crystallography studies identified key amino acid residues in the binding pocket present in human IL-36γ that are absent in human IL-36α. A-552 represents a first-in-class small molecule antagonist of IL-36 signaling that could be used as a chemical tool to further investigate the role of this pathway in inflammatory skin diseases such as psoriasis.

PubMed: 31235749
DOI: 10.1038/s41598-019-45626-w

実験手法

X-RAY DIFFRACTION (2 Å)