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PDBsum entry 4jyg
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Transcription/agonist
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PDB id
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4jyg
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References listed in PDB file
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Key reference
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Title
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An unexpected mode of binding defines bms948 as a full retinoic acid receptor β (rarβ, Nr1b2) selective agonist.
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Authors
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E.Nadendla,
C.Teyssier,
V.Delfosse,
V.Vivat,
G.Krishnasamy,
H.Gronemeyer,
W.Bourguet,
P.Germain.
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Ref.
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Plos One, 2015,
10,
e0123195.
[DOI no: ]
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PubMed id
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Abstract
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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.
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