Ligand-binding regulation of LXR/RXR and LXR/PPAR heterodimerizations: SPR technology-based kinetic analysis correlated with molecular dynamics simulation.
Liver X receptor (LXR) and peroxisome proliferator-activated receptor (PPAR) are two members of nuclear receptors involved in the nutrient metabolisms of dietary fatty acid and cholesterol. They are found to be of cross-talk function in that LXR regulates fatty acid synthesis and PPAR controls fatty acid degradation. LXRs (LXRalpha and LXRbeta) function by forming obligate heterodimers with the retinoid X receptor (RXR), and subsequently binding to specific DNA response elements within the regulatory regions of their target genes. In this work, the kinetic features concerning LXR/RXR and LXR/PPAR interactions have been fully investigated using surface plasmon resonance (SPR) technology. It is found that LXRs could bind to all the three PPAR subtypes, PPARalpha, PPARgamma and PPARdelta with different binding affinities, and such receptor/receptor interactions could be regulated by ligand binding. Moreover, molecular dynamics (MD) simulations were performed on six typical complex models. The results revealed that ligands may increase the interaction energies between the receptor interfaces of the simulated receptor/receptor complexes. The MD results are in agreement with the SPR data. Further analyses on the MD results indicated that the ligand binding might increase the hydrogen bonds between the interfaces of the receptor/receptor complex.
Yue
Liduo
L
Drug Discovery and Design Center, State Key Lab of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Graduate School, Chinese Academy of Sciences, Shanghai 201203, China.
Ye
Fei
F
Gui
Chunshan
C
Luo
Haibin
H
Cai
Jianhua
J
Shen
Jianhua
J
Chen
Kaixian
K
Shen
Xu
X
Jiang
Hualiang
H
D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D007700:Kinetics; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D025941:Protein Interaction Mapping; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020349:Surface Plasmon Resonance
D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047492:Peroxisome Proliferator-Activated Receptors; D018160:Receptors, Cytoplasmic and Nuclear
Mol Endocrinol. 2003 Jul;17(7):1255-67
12730332
Nat Struct Biol. 1996 Jan;3(1):87-94
8548460
J Med Chem. 2000 Feb 24;43(4):527-50
10691680
Curr Opin Biotechnol. 1997 Feb 1;8(1):50-7
9013659
Nature. 1995 Dec 14;378(6558):681-9
7501014
Cell. 2003 Apr 18;113(2):159-70
12705865
Anal Biochem. 2000 Feb 1;278(1):1-13
10640347
Ann N Y Acad Sci. 1995 Jun 12;761:38-49
7625741
J Biol Chem. 2000 Oct 27;275(43):33201-4
10944516
Mol Cell. 2000 Mar;5(3):545-55
10882139
Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):266-71
9874807
Mol Endocrinol. 1995 Dec;9(12):1814-24
8614417
FEBS Lett. 1999 Dec 17;463(3):205-10
10606722
Biochemistry. 1996 Mar 12;35(10):3309-18
8605168
J Mol Biol. 2000 Dec 15;304(5):983-94
11124041
Genes Dev. 1995 May 1;9(9):1033-45
7744246
Cell. 1995 Dec 15;83(6):835-9
8521507
J Am Coll Cardiol. 1998 Nov 15;32(6):1648-56
9822092
J Mol Neurosci. 1996 Spring;7(1):29-39
8835780
J Comput Aided Mol Des. 1996 Jun;10(3):255-62
8808741
Expert Opin Investig Drugs. 1997 Aug;6(8):1025-40
15989661
J Biol Chem. 1995 Jul 28;270(30):18117-22
7629123
FEBS Lett. 1998 Jul 24;431(3):476-80
9714568
Mol Endocrinol. 2003 Jul;17(7):1240-54
12730331
Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10809-13
7971966
Eur J Biochem. 2004 Jan;271(2):386-97
14717706
J Biol Chem. 1998 Nov 20;273(47):31108-12
9813012
J Biol Chem. 1996 Apr 19;271(16):9189-92
8621574
J Mol Biol. 1996 Aug 23;261(3):470-89
8780787
Curr Opin Genet Dev. 1998 Oct;8(5):571-5
9794827
Genes Dev. 1997 Feb 1;11(3):289-98
9030682
Nature. 1995 Jun 1;375(6530):377-82
7760929
Protein Eng. 1995 Feb;8(2):127-34
7630882
J Biol Chem. 1997 Feb 7;272(6):3137-40
9013544
J Mol Biol. 2003 Feb 7;326(1):77-92
12547192
Mol Endocrinol. 1998 Oct;12(10):1594-604
9773982