Retinoid　X　receptor-alpha　(RXR　alpha)　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　RXR　alpha　(tRXR　alpha),　produced　in　tumour　cells,　activates　phosphoinositide　3-kinase　(PI3K)　signalling　by　binding　to　the　p85　alpha　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　tRXR　alpha　tetramers　via　a　＇three-pronged＇　combination　of　canonical　and　non-canonical　mechanisms.　K-80003　binding　has　no　effect　on　tetramerization　of　RXR　alpha,　owing　to　the　head-tail　interaction　that　is　absent　in　tRXR　alpha.　We　also　identify　an　LxxLL　motif　in　p85　alpha,　which　binds　to　the　coactivator-binding　groove　on　tRXR　alpha　and　dissociates　from　tRXR　alpha　upon　tRXR　alpha　tetramerization.　These　results　identify　conformational　selection　as　the　mechanism　for　inhibiting　the　nongenomic　action　of　tRXR　alpha　and　provide　molecular　insights　into　the　development　of　RXR　alpha　cancer　therapeutics.