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Sci. Signal., 16 June 2009
[DOI: 10.1126/scisignal.275re4]

The Vitamin D Sterol–Vitamin D Receptor Ensemble Model Offers Unique Insights into Both Genomic and Rapid-Response Signaling (Movies)

Mathew T. Mizwicki* and Anthony W. Norman

*Corresponding author. E-mail, mathew.mizwicki{at}ucr.edu

Description

These animations show interactions between the vitamin D sterol (VDS) 1α,25(OH)2D3 (1,25D) and the vitamin D receptor (VDR) alternate (VDR-AP) and genomic (VDR-GP) ligand-binding pockets.

Movie 1: 1,25D A-ring–first VDR-AP complex dynamics. Portions of the VDR molecule that are believed to be involved in ligand binding have been rendered to show their secondary structure (ribbon) and R-group configurations. The ribbon has been colored to show the relative hydrophobicity of the R groups (blue, hydrophobic; red, polar charged; pink, polar uncharged). The middle helix represents helix 3 of the VDR. To the left of H3 is the H11-H12 region, and to the right is the H2 β-sheet region of the VDR. The transparent green surface depicts the VDR-c1 ligand-binding channel. Generally speaking, the VDR-AP is located to the right and the VDR-GP to the left of H3 in the movie.

This movie highlights the complex dynamics of the 1,25D molecule entering the VDR-AP A-ring–first. As the movie plays, three frames have been highlighted by slowing the frame transition in the animated GIF. The three frames, in order of appearance, represent the stable complex formation between each of three 1,25D conformational isomers (population A, β chair, cis; α chair, trans; and β chair, trans) and the VDR-AP. All three of these complexes have near-identical stability when complexed to the VDR-AP; therefore, they collectively serve as nongenomic agonists (1, 2). The animated GIF was generated from VDS-VDR docking simulations that allow for flexibility in both the VDS and VDR R groups. Therefore, the true dynamics of the system are overgeneralized, given that VDR backbone atoms are restrained from moving. Nonetheless, it treats both the VDS and VDR as flexible bodies.

[Play Movie 1]

Movie 2: Transition of 1,25D from the VDR-AP to the VDR-GP through side chain–first entrance into both. Portions of the VDR molecule that are believed to be involved in ligand binding have been rendered to show their secondary structure (ribbon) and R-group configurations. The ribbon has been colored to show the relative hydrophobicity of the R groups (blue, hydrophobic; red, polar charged; pink, polar uncharged). The middle helix represents helix 3 of the VDR. To the left of H3 is the H11-H12 region, and to the right is the H2 β-sheet region of the VDR. The transparent green surface depicts the VDR-c1 ligand-binding channel. Generally speaking, the VDR-AP is located to the right and the VDR-GP to the left of H3 in the movie.

This movie highlights how the VDR-AP can serve as a selectivity filter for the VDR-GP. The movie starts by showing 1,25D oriented in the VDR-AP side chain–first. As stated in the text, this orientation is energetically less favored relative to the A-ring–first complex, given that the A-ring domain (overlapping regions of the VDR-AP and VDR-GP) is predominantly a hydrophilic environment. The movie continues by showing the ability of the flexible 1,25D molecule to move from the VDR-AP to the VDR-GP.

The movie slows down to highlight four frames of the animated GIF. The first of these frames, in order of appearance, shows the population B (α chair, trans) 1,25D conformational isomer occupying portions of both the VDR-AP and VDR-GP.

The second of these four frames depicts a complex where the side chain of the 1,25D population B (α-twist boat, cis) conformational isomer is extending into the VDR-GP.

The next two frames depict 1,25D conformational isomers complexed to the VDR-GP, where the A-ring and seco-B-ring configurations are identical to those observed in the 1,25D-VDR x-ray structure. The side-chain conformation of the 1,25D molecule takes on a population A and population B conformation (the orientation observed in the 1,25D-VDR x-ray complex) in these two frames, respectively. These two frames have also been rendered so that the wire frames of the R groups are colored green and the orientation of the two frames adjusted slightly to highlight them.

The animated GIF was generated from VDS-VDR docking simulations that allow for flexibility in both the VDS and VDR R groups. Therefore, the true dynamics of the system are overgeneralized, given that VDR backbone atoms are restrained from moving. Nonetheless, it treats the VDS and VDR as flexible bodies.

[Play Movie 2]

References

  1. M. T. Mizwicki, D. Keidel, C. M. Bula, J. E. Bishop, L. P. Zanello, J. M. Wurtz, D. Moras, A. W. Norman, Identification of an alternative ligand-binding pocket in the nuclear vitamin D receptor and its functional importance in 1α,25(OH)2-vitamin D3 signaling. Proc. Natl. Acad. Sci. U.S.A. 101, 12876–12881 (2004).
  2. A. W. Norman, M. T. Mizwicki, D. P. G. Norman, Steroid hormone rapid actions, membrane receptors and a conformational ensemble model. Nat. Rev. Drug Discov. 3, 27–41 (2004).

Technical Details

Format: Gif

Requirements: Any Web Browser


Citation: M. T. Mizwicki, A. W. Norman, The Vitamin D Sterol–Vitamin D Receptor Ensemble Model Offers Unique Insights into Both Genomic and Rapid-Response Signaling. Sci. Signal. 2, re4 (2009).

© 2009 American Association for the Advancement of Science


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