1xb7
|
X-ray structure of ERRalpha LBD in complex with a PGC-1alpha peptide at 2.5A resolution
OverviewOverview
The crystal structure of the ligand binding domain (LBD) of the, estrogen-related receptor alpha (ERRalpha, NR3B1) complexed with a, coactivator peptide from peroxisome proliferator-activated receptor, coactivator-1alpha (PGC-1alpha) reveals a transcriptionally active, conformation in the absence of a ligand. This is the first x-ray structure, of ERRalpha LBD, solved to a resolution of 2.5 A, and the first structure, of a PGC-1alpha complex. The putative ligand binding pocket (LBP) of, ERRalpha is almost completely occupied by side chains, in particular with, the bulky side chain of Phe328 (corresponding to Ala272 in ERRgamma and, Ala350 in estrogen receptor alpha). Therefore, a ligand of a size, equivalent to more than approximately 4 carbon atoms could only bind in, the LBP, if ERRalpha would undergo a major conformational change (in, particular the ligand would displace H12 from its agonist position). The, x-ray structure thus provides strong evidence for ligand-independent, transcriptional activation by ERRalpha. The interactions of PGC-1alpha, with ERRalpha also reveal for the first time the atomic details of how a, coactivator peptide containing an inverted LXXLL motif (namely a LLXYL, motif) binds to a LBD. In addition, we show that a PGC-1alpha peptide, containing this nuclear box motif from the L3 site binds ERRalpha LBD with, a higher affinity than a peptide containing a steroid receptor, coactivator-1 motif and that the affinity is further enhanced when all, three leucine-rich regions of PGC-1alpha are present.
DiseaseDisease
Known diseases associated with this structure: Lipodystrophy, familial partial, with decreased subcutaneous fat of face and neck OMIM:[604517], Obesity, variation in OMIM:[608886]
About this StructureAbout this Structure
1XB7 is a Protein complex structure of sequences from Homo sapiens with IOD as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Evidence for ligand-independent transcriptional activation of the human estrogen-related receptor alpha (ERRalpha): crystal structure of ERRalpha ligand binding domain in complex with peroxisome proliferator-activated receptor coactivator-1alpha., Kallen J, Schlaeppi JM, Bitsch F, Filipuzzi I, Schilb A, Riou V, Graham A, Strauss A, Geiser M, Fournier B, J Biol Chem. 2004 Nov 19;279(47):49330-7. Epub 2004 Aug 26. PMID:15337744
Page seeded by OCA on Mon Nov 12 20:03:04 2007