Active nuclear receptors exhibit highly correlated AF-2 domain motions

Denise G. Teotico, Monica L. Frazier, Feng Ding, Nikolay V. Dokholyan, Brenda R.S. Temple, Matthew R. Redinbo

Research output: Contribution to journalArticle

35 Scopus citations

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.

Original languageEnglish (US)
Article numbere1000111
JournalPLoS computational biology
Volume4
Issue number7
DOIs
StatePublished - Jul 2008

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Ecology
  • Molecular Biology
  • Genetics
  • Cellular and Molecular Neuroscience
  • Computational Theory and Mathematics

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  • Cite this

    Teotico, D. G., Frazier, M. L., Ding, F., Dokholyan, N. V., Temple, B. R. S., & Redinbo, M. R. (2008). Active nuclear receptors exhibit highly correlated AF-2 domain motions. PLoS computational biology, 4(7), [e1000111]. https://doi.org/10.1371/journal.pcbi.1000111