Millisecond to microsecond time scale dynamics of the retinoid X and retinoic acid receptor DNA-binding domains and dimeric complex formation

The all-trans retinoic acid and 9-cis retinoic acid receptors (RAR and RXR, respectively) belong to a family of ligand inducible transcription factors , which exert their effect via binding to hormone response elements. Both a re members of the class II sub-family of nuclear receptors, which bind DNA as dimers, on tandem repeats of a hexamer motif separated by a variable spa cer. The variability in spacer length and the head-to-tail organization of the hormone response elements result in different protein-protein interacti ons in each of the complexes. We show that the zinc-coordinating loop regio ns of RXR and RAR DNA-binding domains exhibit dynamics on the millisecond t o microsecond time scale. The highly dynamic second zinc finger of RXR cons titutes the primary protein-protein interface in many nuclear receptor asse mblies on DNA. Dynamics is also observed in the first and second zinc finge rs of RAR, which are implicated in dimeric interactions with RXR on respons e elements with spacers of 5 base pairs and 1 base pair, respectively. The striking correspondence between the regions that exhibit conformational exc hange and the dimer interfaces of the proteins complexed with DNA suggests a functional role for the dynamics. The observed flexibility may allow the proteins to adapt to various partners and with different orientations upon assembly on DNA. Furthermore, the more extensive dynamics observed for RXR may reflect the greater ability of this protein to modulate its interaction surface since it participates in a wide variety of receptor complexes.