4YMQ

X-ray co-structure of nuclear receptor ROR-GAMMAT + SRC2 peptide with a benzothiadiazole dioxide inverse agonist

Summary for 4YMQ

• Entry DOI: 10.2210/pdb4ymq/pdb
• Descriptor: Nuclear receptor ROR-gamma, SODIUM ION, GLYCEROL, ... (5 entities in total)
• Functional Keywords: rorgt, nuclear hormone receptor, benzothiadiazole dioxide, inverse agonist
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P51449
• Total number of polymer chains: 1
• Total formula weight: 33155.09

Authors

li, X. (deposition date: 2015-03-07, release date: 2015-04-22, Last modification date: 2024-02-28)

Primary citation

Muegge, I.,Collin, D.,Cook, B.,Hill-Drzewi, M.,Horan, J.,Kugler, S.,Labadia, M.,Li, X.,Smith, L.,Zhang, Y.
Discovery of 1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide analogs as new RORC modulators.
Bioorg.Med.Chem.Lett., 25:1892-1895, 2015

PubMed Abstract: Structure-based and pharmacophore-based virtual screening in combination with combinatorial chemistry and X-ray crystallography led to the discovery of a new class of benzothiadiazole dioxide analogs with functional activity as RORC inverse agonists. The early RORC SAR compound 14 exhibited RORC inhibition in a cell based reporter gene assay of 5.7 μM and bound to RORC with an affinity of 1.6 μM in a fluorescence polarization assay displacing a ligand binding site probe. Crystallography confirmed the binding mode of the compound in the ligand binding domain displaying the engagement of a novel sub pocket close to Ser404. Subsequent optimization yielded compounds with enhanced RORC inverse agonist activity. The most active compound 19 showed an IC50 of 440 nM in a human PBMC assay.

PubMed: 25840886
DOI: 10.1016/j.bmcl.2015.03.042

Experimental method

X-RAY DIFFRACTION (2 Å)