8DYG

IL17A homodimer bound to Compound 7

8DYG の概要

• エントリーDOI: 10.2210/pdb8dyg/pdb
• 分子名称: Interleukin-17A, (5P)-2-hydroxy-5-(6-methylquinolin-5-yl)benzoic acid (3 entities in total)
• 機能のキーワード: dimer, fragment, inhibitor, antagonist, cytokine
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 29633.27

構造登録者

Argiriadi, M.A.,Goedken, E.R. (登録日: 2022-08-04, 公開日: 2022-09-07, 最終更新日: 2023-10-18)

主引用文献

Goedken, E.R.,Argiriadi, M.A.,Dietrich, J.D.,Petros, A.M.,Krishnan, N.,Panchal, S.C.,Qiu, W.,Wu, H.,Zhu, H.,Adams, A.M.,Bodelle, P.M.,Goguen, L.,Richardson, P.L.,Slivka, P.F.,Srikumaran, M.,Upadhyay, A.K.,Wu, B.,Judge, R.A.,Vasudevan, A.,Gopalakrishnan, S.M.,Cox, P.B.,Stoll, V.S.,Sun, C.
Identification and structure-based drug design of cell-active inhibitors of interleukin 17A at a novel C-terminal site.
Sci Rep, 12:14561-14561, 2022

PubMed Abstract: Anti-IL17A therapies have proven effective for numerous inflammatory diseases including psoriasis, axial spondylitis and psoriatic arthritis. Modulating and/or antagonizing protein-protein interactions of IL17A cytokine binding to its cell surface receptors with oral therapies offers the promise to bring forward biologics-like efficacy in a pill to patients. We used an NMR-based fragment screen of recombinant IL17A to uncover starting points for small molecule IL17A antagonist discovery. By examining chemical shift perturbations in 2D [H, C-HSQC] spectra of isotopically labeled IL17A, we discovered fragments binding the cytokine at a previously undescribed site near the IL17A C-terminal region, albeit with weak affinity (> 250 µM). Importantly this binding location was distinct from previously known chemical matter modulating cytokine responses. Subsequently through analog screening, we identified related compounds that bound symmetrically in this novel site with two copies. From this observation we employed a linking strategy via structure-based drug design and obtained compounds with increased binding affinity (< 50 nM) and showed functional inhibition of IL17A-induced cellular signaling (IC~1 µM). We also describe a fluorescence-based probe molecule suitable to discern/screen for additional molecules binding in this C-terminal site.

PubMed: 36028520
DOI: 10.1038/s41598-022-18760-1

実験手法

X-RAY DIFFRACTION (1.49 Å)