4JYI

Crystal structure of RARbeta LBD in complex with selective partial agonist BMS641 [3-chloro-4-[(E)-2-(5,5-dimethyl-8-phenyl-5,6-dihydronaphthalen-2-yl)ethenyl]benzoic acid]

Summary for 4JYI

• Entry DOI: 10.2210/pdb4jyi/pdb
• Related: 1XAP 4DM6 4DM8 4JYG 4JYH
• Descriptor: Retinoic acid receptor beta, Nuclear receptor coactivator 1, 3-chloro-4-[(E)-2-(5,5-dimethyl-8-phenyl-5,6-dihydronaphthalen-2-yl)ethenyl]benzoic acid, ... (5 entities in total)
• Functional Keywords: ligand binding domain, nuclear hormone receptor, transcription-agonist complex, transcription/agonist
• Biological source: Homo sapiens (human); More
• Cellular location: Isoform Beta-1: Nucleus. Isoform Beta-2: Nucleus. Isoform Beta-4: Cytoplasm: P10826; Nucleus : Q15788
• Total number of polymer chains: 4
• Total formula weight: 64596.71

Authors

Nadendla, E.K.,Teyssier, C.,Germain, P.,Delfosse, V.,Bourguet, W. (deposition date: 2013-03-29, release date: 2014-03-19, Last modification date: 2024-02-28)

Primary citation

Nadendla, E.,Teyssier, C.,Delfosse, V.,Vivat, V.,Krishnasamy, G.,Gronemeyer, H.,Bourguet, W.,Germain, P.
An Unexpected Mode Of Binding Defines BMS948 as A Full Retinoic Acid Receptor beta (RAR beta , NR1B2) Selective Agonist.
Plos One, 10:e0123195-e0123195, 2015

PubMed Abstract: Retinoic acid is an important regulator of cell differentiation which plays major roles in embryonic development and tissue remodeling. The biological action of retinoic acid is mediated by three nuclear receptors denoted RARα, β and γ. Multiple studies support that RARβ possesses functional characteristics of a tumor suppressor and indeed, its expression is frequently lost in neoplastic tissues. However, it has been recently reported that RARβ could also play a role in mammary gland tumorigenesis, thus demonstrating the important but yet incompletely understood function of this receptor in cancer development. As a consequence, there is a great need for RARβ-selective agonists and antagonists as tools to facilitate the pharmacological analysis of this protein in vitro and in vivo as well as for potential therapeutic interventions. Here we provide experimental evidences that the novel synthetic retinoid BMS948 is an RARβ-selective ligand exhibiting a full transcriptional agonistic activity and activating RARβ as efficiently as the reference agonist TTNPB. In addition, we solved the crystal structures of the RARβ ligand-binding domain in complex with BMS948 and two related compounds, BMS641 and BMS411. These structures provided a rationale to explain how a single retinoid can be at the same time an RARα antagonist and an RARβ full agonist, and revealed the structural basis of partial agonism. Finally, in addition to revealing that a flip by 180° of the amide linker, that usually confers RARα selectivity, accounts for the RARβ selectivity of BMS948, the structural analysis uncovers guidelines for the rational design of RARβ-selective antagonists.

PubMed: 25933005
DOI: 10.1371/journal.pone.0123195

Experimental method

X-RAY DIFFRACTION (1.9 Å)