@article{10.1371/journal.pcbi.1000111, doi = {10.1371/journal.pcbi.1000111}, author = {Teotico, Denise G. AND Frazier, Monica L. AND Ding, Feng AND Dokholyan, Nikolay V. AND Temple, Brenda R. S. AND Redinbo, Matthew R.}, journal = {PLOS Computational Biology}, publisher = {Public Library of Science}, title = {Active Nuclear Receptors Exhibit Highly Correlated AF-2 Domain Motions}, year = {2008}, month = {07}, volume = {4}, url = {https://doi.org/10.1371/journal.pcbi.1000111}, pages = {1-13}, abstract = {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 Å 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.}, number = {7}, }