Structural highlights
Disease
[NCOA2_HUMAN] Note=Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation.
Function
[NR5A2_HUMAN] Binds to the sequence element 5'-AACGACCGACCTTGAG-3' of the enhancer II of hepatitis B virus genes, a critical cis-element of their expression and regulation. May be responsible for the liver-specific activity of enhancer II, probably in combination with other hepatocyte transcription factors. Key regulator of cholesterol 7-alpha-hydroxylase gene (CYP7A) expression in liver. May also contribute to the regulation of pancreas-specific genes and play important roles in embryonic development. [NCOA2_HUMAN] Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues.[1]
Publication Abstract from PubMed
As a key regulator of metabolism and inflammation, the orphan nuclear hormone receptor, Liver Receptor Homolog-1 (LRH-1), has potential as a therapeutic target for diabetes, nonalcoholic fatty liver disease, and inflammatory bowel diseases. Discovery of LRH-1 modulators has been difficult, in part due to the tendency for synthetic compounds to bind unpredictably within the lipophilic binding pocket. Using a structure-guided approach, we exploited a newly-discovered polar interaction to lock agonists in a consistent orientation. This enabled the discovery of the first low nanomolar LRH-1 agonist, one hundred times more potent than the best previous modulator. We elucidate a novel mechanism of action that relies upon specific polar interactions deep in the LRH-1 binding pocket. In an organoid model of inflammatory bowel disease, the new agonist increases expression of LRH-1-conrolled steroidogenic genes and promotes anti-inflammatory gene expression changes. These studies constitute major progress in developing LRH-1 modulators with potential clinical utility.
Development of the first low nanomolar Liver Receptor Homolog-1 agonist through structure-guided design.,Mays S, Flynn AR, Cornelison J, Okafor CD, Wang H, Wang G, Huang X, Donaldson H, Millings E, Polavarapu R, Moore D, Calvert J, Jui NT, Ortlund EA J Med Chem. 2019 Aug 16. doi: 10.1021/acs.jmedchem.9b00753. PMID:31419141[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Voegel JJ, Heine MJ, Tini M, Vivat V, Chambon P, Gronemeyer H. The coactivator TIF2 contains three nuclear receptor-binding motifs and mediates transactivation through CBP binding-dependent and -independent pathways. EMBO J. 1998 Jan 15;17(2):507-19. PMID:9430642 doi:10.1093/emboj/17.2.507
- ↑ Mays S, Flynn AR, Cornelison J, Okafor CD, Wang H, Wang G, Huang X, Donaldson H, Millings E, Polavarapu R, Moore D, Calvert J, Jui NT, Ortlund EA. Development of the first low nanomolar Liver Receptor Homolog-1 agonist through structure-guided design. J Med Chem. 2019 Aug 16. doi: 10.1021/acs.jmedchem.9b00753. PMID:31419141 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00753
