X-ray crystal structure of the liver X receptor beta ligand binding domain: regulation by a histidine-tryptophan switch.
The x-ray crystal structures of the human liver X receptor beta ligand binding domain complexed to sterol and nonsterol agonists revealed a perpendicular histidinetryptophan switch that holds the receptor in its active conformation. Hydrogen bonding interactions with the ligand act to position the His-435 imidazole ring against the Trp-457 indole ring, allowing an electrostatic interaction that holds the AF2 helix in the active position. The neutral oxysterol 24(S),25-epoxycholesterol accepts a hydrogen bond from His-435 that positions the imidazole ring of the histidine above the pyrrole ring of the tryptophan. In contrast, the acidic T0901317 hydroxyl group makes a shorter hydrogen bond with His-435 that pulls the imidazole over the electron-rich benzene ring of the tryptophan, possibly strengthening the electrostatic interaction. Point mutagenesis of Trp-457 supports the observation that the ligand-histidine-tryptophan coupling is different between the two ligands. The lipophilic liver X receptor ligand-binding pocket is larger than the corresponding steroid hormone receptors, which allows T0901317 to adopt two distinct conformations. These results provide a molecular basis for liver X receptor activation by a wide range of endogenous neutral and acidic ligands.
GlaxoSmithKline, Discovery Research, Research Triangle Park, NC 27709, USA. shawn.p.williams@gsk.com
Shawn
S
Williams
Randy K
RK
Bledsoe
Jon L
JL
Collins
Sharon
S
Boggs
Millard H
MH
Lambert
Ann B
AB
Miller
John
J
Moore
David D
DD
McKee
Linda
L
Moore
Jason
J
Nichols
Derek
D
Parks
Mike
M
Watson
Bruce
B
Wisely
Timothy M
TM
Willson
D000924:Anticholesteremic Agents / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins; D006639:Histidine / Q000737:chemistry; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D008024:Ligands; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D057093:Orphan Nuclear Receptors; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides; D014364:Tryptophan / Q000737:chemistry; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000924:Anticholesteremic Agents; D002784:Cholesterol; D004268:DNA-Binding Proteins; D006639:Histidine; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D013449:Sulfonamides; D014364:Tryptophan; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C028358:24,25-epoxycholesterol