9PEE

Cryo-EM structure of CCR6 bound by PF-07054894 and OXM2

これはPDB形式変換不可エントリーです。

9PEE の概要

• エントリーDOI: 10.2210/pdb9pee/pdb
• EMDBエントリー: 71559
• 分子名称: Human CCR6, anti-BRIL Fab Light chain, anti-BRIL Fab Nanobody, ... (6 entities in total)
• 機能のキーワード: gpcr, complex, antagonist, membrane protein
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 125428.63

構造登録者

Wasilko, D.J.,Wu, H. (登録日: 2025-07-02, 公開日: 2025-10-01, 最終更新日: 2025-10-22)

主引用文献

Schnute, M.E.,Wu, H.,Trujillo, J.I.,Li, W.,Wasilko, D.J.,Alley, J.,Arnold, E.P.,Bagley, S.W.,Berstein, G.,Blakemore, D.C.,Bundesmann, M.W.,Chinigo, G.M.,Choi, C.,Cooke, R.,Crouse, K.,Dermenci, A.,Dickinson, T.,Flick, A.,Frisbie, R.K.,Garcia-Irizarry, C.,Gerstenberger, B.S.,Hepworth, D.,Kaila, N.,Kung, D.W.,Lamb, D.,Lavergne, S.Y.,Limburg, D.C.,Liu, S.,Lombardo, V.M.,Mondal, P.K.,Mousseau, J.J.,Narayanan, A.,Niljianskul, N.,Nuhant, P.,Pan, S.,Primiano, M.J.,Rappas, M.,Schmitt, D.C.,Steyn, S.J.,Unwalla, R.,Vasa, D.,Vazquez, M.L.,Vincent, F.,Yang, X.,Thorarensen, A.
Discovery of PF-07054894, a Potent Squaramide-Based CCR6 Antagonist Displaying High CXCR2 Selectivity.
J.Med.Chem., 68:20689-20716, 2025

PubMed Abstract: The G protein-coupled receptor (GPCR) CCR6 mediates the migration of pathogenic immune cells to the site of inflammation in response to the chemokine CCL20. CCR6 is an attractive target for the treatment of chronic autoimmune disease as antagonism of the receptor is expected to block CCL20-mediated immune cell recruitment. High-throughput-screening identified a squaramide-based, allosteric antagonist of CCR6 that potently inhibited CCL20-mediated T cell chemotaxis, but it also inhibited CXCL1-mediated neutrophil chemotaxis through CXCR2 antagonism. Lead optimization achieved differentiation from CXCR2 through identification of a methyl substituent-dependent selectivity switch or "magic methyl for selectivity". The mechanism for this effect is rooted in different antagonist-induced ligand-receptor behaviors, insurmountable for CCR6 and surmountable for CXCR2. Herein, we report the discovery and preclinical evaluation of the CCR6 antagonist PF-07054894 () which has advanced to clinical trials as a first in class approach targeting the receptor.

PubMed: 40977184
DOI: 10.1021/acs.jmedchem.5c01946

実験手法

ELECTRON MICROSCOPY (3.35 Å)