Peroxisome proliferator-activated gamma coactivator 1- (PGC1) regulates energy metabolism by directly interacting with transcription factors to modulate gene expression. Among the PGC1 binding partners is liver receptor homolog 1 (LRH-1; NR5A2), an orphan nuclear hormone receptor that controls lipid and glucose homeostasis. Although PGC1 is known to bind and activate LRH-1, mechanisms through which PGC1 changes LRH-1 conformation to drive transcription are unknown. Here, we used biochemical and structural methods to interrogate the LRH-1-PGC1 complex. Purified, full-length LRH-1, as well as isolated ligand binding domain, bound to PGC1 with higher affinity than to the coactivator, nuclear receptor coactivator-2 (Tif2), in coregulator peptide recruitment assays. We present the first crystal structure of the LRH-1-PGC1 complex, which depicts several hydrophobic contacts and a strong charge clamp at the interface between these partners. In molecular dynamics simulations, PGC1 induced correlated atomic motion throughout the entire LRH-1 activation function surface, which was dependent on charge-clamp formation. In contrast, Tif2 induced weaker signaling at the activation function surface than PGC1 but promoted allosteric signaling from the helix 6/-sheet region of LRH-1 to the activation function surface. These studies are the first to probe mechanisms underlying the LRH-1-PGC1 interaction and may illuminate strategies for selective therapeutic targeting of PGC1-dependent LRH-1 signaling pathways.
Oct4 is a transcription factor required for maintaining pluripotency and self-renewal in stem cells. Prior to differentiation, Oct4 must be silenced to allow for the development of the three germ layers in the developing embryo. This fine-tuning is controlled by the nuclear receptors, liver receptor homolog-1 and germ cell nuclear factor. Liver receptor homolog-1 is responsible for driving the expression of Oct4 where germ cell nuclear factor represses its expression upon differentiation. Both receptors bind to a DR0 motif located within the Oct4 promoter. Here, we present the first structure of mouse germ cell nuclear factor DNA binding domain in complex with the Oct4 DR0. The overall structure revealed two molecules bound in a head-to-tail fashion on opposite sides of the DNA. Additionally, we solved the structure of the human liver receptor homolog-1 DNA binding domain bound to the same element. We explore the structural elements that govern Oct4 recognition by these two nuclear receptors.
The apo structure of N5‐carboxyaminoimidazole ribonucleotide synthase (PurK) from Bacillus anthracis (baPurK) with Mg2+ in the active site is reported at 1.96 Å resolution. PurK is an enzyme in the purine‐biosynthetic pathway, unique to prokaryotes, that converts 5‐aminoimidazole ribonucleotide to N5‐carboxyaminoimidazole ribonucleotide and has been suggested as a potential antimicrobial drug target. Two interesting features of baPurK are a flexible B‐loop (residues 149/150–157) that is in close contact with the active site and the binding of Mg2+ to the active site without additional ligands.
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