Direct repeated structure RXR monodimerization
Distance & polarization
Crosstalk of NRs—Subordination and different heterodimerization synergy of RXR interface→some partners can form
PRINCIPLES FOR MODULATION OF THE NUCLEAR RECEPTOR
MaYue of XMU 2013.6.4
1、Selectivity of NR by ligands 2、Transconformation of NRs by ligands 3、Crosstalk of NRs 4、Transcription initiated by NRs
Glu353 Arg394 His524
“L”
ERα & ERβ
Transconformation of NRs by ligands——mouse trap mechanism
apo
SR11237
holo
hydrophobic surface, involving residues from H3, H4 and H12
Transcription initiated by NRs
ＴＨＡＮＫ ＹＯＵ
more stable heterodimers with RXR than can others.
For instance, the presence of excess LXR or its ligands reduces DNA binding of PPARα/RXRα to PPRE, which inhibits PPAR signaling and suppresses transcription of lipid degradation genes. Vice versa.
Transconformation of NRs by ligands——mouse trap mechanism
Conformation characteristic of NRs by partial agonist
high cellular co-activator levels
RARγ
active position
short helical LXXLL motifs (NR boxes)
Agonist-induced conformational change and RXR activation
Transconformation of NRs by ligands——mouse trap mechanism
partners for PPARs,VDR,TR,LXR,RAR
an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist.
Selectivity of NR by ligands
ligand Steric hindrance hydrogen bond hydrophobic bond Van der Waals' force LBP of NR
repulsive steric interaction between vinyl group of the ligand (yellow star) and Leu384 in ERα
RXRα
active conformation might be transiently stabilized
Crosstalk of NRs—Subordination and synergy of RXR
Palindrome structure Steroid dimerizstructure RXR heterdimerization
This inhibition can be relieved by the addition of RXRα, suggesting that competition for and sequestration of RXR is a contributor to cross-talk between the LXR and PPAR signaling pathways.
RXR is unable to respond to RXRselective ligands in the absence of an RAR ligand. The phonomonen, reffered to as RXR subodination or silencing, is biological important as it avoids simultaneous activation of RA, TH,VD3 signaling pathway
Crosstalk of NRs—Subordination and synergy of RXR RXRs are dimerization
1、CoR binding RAR 2、CoR & CoA are exclusive 3、ligand induced clearance of Co-rugulator