4jyi | pdb_00004jyi
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]
Structural highlights
FunctionRARB_HUMAN Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence or presence of hormone ligand, acts mainly as an activator of gene expression due to weak binding to corepressors. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function.[1] Publication Abstract from PubMedRetinoic 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 RARalpha, beta and gamma. Multiple studies support that RARbeta possesses functional characteristics of a tumor suppressor and indeed, its expression is frequently lost in neoplastic tissues. However, it has been recently reported that RARbeta 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 RARbeta-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 RARbeta-selective ligand exhibiting a full transcriptional agonistic activity and activating RARbeta as efficiently as the reference agonist TTNPB. In addition, we solved the crystal structures of the RARbeta 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 RARalpha antagonist and an RARbeta full agonist, and revealed the structural basis of partial agonism. Finally, in addition to revealing that a flip by 180 degrees of the amide linker, that usually confers RARalpha selectivity, accounts for the RARbeta selectivity of BMS948, the structural analysis uncovers guidelines for the rational design of RARbeta-selective antagonists. An Unexpected Mode Of Binding Defines BMS948 as A Full Retinoic Acid Receptor beta (RARbeta, NR1B2) Selective Agonist.,Nadendla E, Teyssier C, Delfosse V, Vivat V, Krishnasamy G, Gronemeyer H, Bourguet W, Germain P PLoS One. 2015 May 1;10(5):e0123195. doi: 10.1371/journal.pone.0123195., eCollection 2015. PMID:25933005[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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