Retinoid　X　receptor-alpha　(RXRα)　binds　to　DNA　either　as　homodimers　or　heterodimers,　but　it　also　forms　homotetramers　whose　function　is　poorly　defined.　We　previously　discovered　that　an　N-terminally-cleaved　form　of　RXRα　(tRXRα),　produced　in　tumour　cells,　activates　phosphoinositide　3-kinase　(PI3K)　signalling　by　binding　to　the　p85α　subunit　of　PI3K　and　that　K-80003,　an　anti-cancer　agent,　inhibits　this　process.　Here,　we　report　through　crystallographic　and　biochemical　studies　that　K-80003　binds　to　and　stabilizes　tRXRα　tetramers　via　a　＇three-pronged＇　combination　of　canonical　and　non-canonical　mechanisms.　K-80003　binding　has　no　effect　on　tetramerization　of　RXRα,　owing　to　the　head-tail　interaction　that　is　absent　in　tRXRα.　We　also　identify　an　LxxLL　motif　in　p85α,　which　binds　to　the　coactivator-binding　groove　on　tRXRα　and　dissociates　from　tRXRα　upon　tRXRα　tetramerization.　These　results　identify　conformational　selection　as　the　mechanism　for　inhibiting　the　nongenomic　action　of　tRXRα　and　provide　molecular　insights　into　the　development　of　RXRα　cancer　therapeutics.　©　2017　The　Author(s).