Active nuclear receptors exhibit highly correlated AF-2 domain motions.
| Autor: | Denise G Teotico, Monica L Frazier, Feng Ding, Nikolay V Dokholyan, Brenda R S Temple, Matthew R Redinbo |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: | |
| Zdroj: | PLoS Computational Biology, Vol 4, Iss 7, p e1000111 (2008) |
| Druh dokumentu: | article |
| ISSN: | 1553-734X 1553-7358 |
| DOI: | 10.1371/journal.pcbi.1000111 |
| Popis: | Nuclear receptor ligand binding domains (LBDs) convert ligand binding events into changes in gene expression by recruiting transcriptional coregulators to a conserved activation function-2 (AF-2) surface. While most nuclear receptor LBDs form homo- or heterodimers, the human nuclear receptor pregnane X receptor (PXR) forms a unique and essential homodimer and is proposed to assemble into a functional heterotetramer with the retinoid X receptor (RXR). How the homodimer interface, which is located 30 A from the AF-2, would affect function at this critical surface has remained unclear. By using 20- to 30-ns molecular dynamics simulations on PXR in various oligomerization states, we observed a remarkably high degree of correlated motion in the PXR-RXR heterotetramer, most notably in the four helices that create the AF-2 domain. The function of such correlation may be to create "active-capable" receptor complexes that are ready to bind to transcriptional coactivators. Indeed, we found in additional simulations that active-capable receptor complexes involving other orphan or steroid nuclear receptors also exhibit highly correlated AF-2 domain motions. We further propose a mechanism for the transmission of long-range motions through the nuclear receptor LBD to the AF-2 surface. Taken together, our findings indicate that long-range motions within the LBD scaffold are critical to nuclear receptor function by promoting a mobile AF-2 state ready to bind coactivators. |
| Databáze: | Directory of Open Access Journals |
| Externí odkaz: |
|