5K13

Crystal structure of the RAR alpha ligand-binding domain in complex with an antagonist

Summary for 5K13

• Entry DOI: 10.2210/pdb5k13/pdb
• Descriptor: Retinoic acid receptor alpha, 4-{5-(3-tert-butylphenyl)-1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-3-yl}benzoic acid (3 entities in total)
• Functional Keywords: nhr ligand-binding domain, antagonist, transcription
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: P10276
• Total number of polymer chains: 1
• Total formula weight: 28163.69

Authors

Wang, Y.,Stout, S.L. (deposition date: 2016-05-17, release date: 2016-06-22, Last modification date: 2023-09-27)

Primary citation

Hughes, N.E.,Bleisch, T.J.,Jones, S.A.,Richardson, T.I.,Doti, R.A.,Wang, Y.,Stout, S.L.,Durst, G.L.,Chambers, M.G.,Oskins, J.L.,Lin, C.,Adams, L.A.,Page, T.J.,Barr, R.J.,Zink, R.W.,Osborne, H.,Montrose-Rafizadeh, C.,Norman, B.H.
Identification of potent and selective retinoic acid receptor gamma (RAR gamma ) antagonists for the treatment of osteoarthritis pain using structure based drug design.
Bioorg.Med.Chem.Lett., 26:3274-3277, 2016

PubMed Abstract: A series of triaryl pyrazoles were identified as potent pan antagonists for the retinoic acid receptors (RARs) α, β and γ. X-ray crystallography and structure-based drug design were used to improve selectivity for RARγ by targeting residue differences in the ligand binding pockets of these receptors. This resulted in the discovery of novel antagonists which maintained RARγ potency but were greater than 500-fold selective versus RARα and RARβ. The potent and selective RARγ antagonist LY2955303 demonstrated good pharmacokinetic properties and was efficacious in the MIA model of osteoarthritis-like joint pain. This compound demonstrated an improved margin to RARα-mediated adverse effects.

PubMed: 27261179
DOI: 10.1016/j.bmcl.2016.05.056

Experimental method

X-RAY DIFFRACTION (1.85 Å)