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Crystal Report 8.0.rar
Assessing the physical connections and allosteric communications in multi-domain nuclear receptor (NR) polypeptides has remained challenging, with few crystal structures available to show their overall structural organizations. Here we report the quaternary architecture of multi-domain retinoic acid receptor β-retinoic X receptor α (RARβ-RXRα) heterodimer bound to DNA, ligands and coactivator peptides, examined through crystallographic, hydrogen-deuterium exchange mass spectrometry, mutagenesis and functional studies ...
Assessing the physical connections and allosteric communications in multi-domain nuclear receptor (NR) polypeptides has remained challenging, with few crystal structures available to show their overall structural organizations. Here we report the quaternary architecture of multi-domain retinoic acid receptor β-retinoic X receptor α (RARβ-RXRα) heterodimer bound to DNA, ligands and coactivator peptides, examined through crystallographic, hydrogen-deuterium exchange mass spectrometry, mutagenesis and functional studies. The RARβ ligand-binding domain (LBD) and DNA-binding domain (DBD) are physically connected to foster allosteric signal transmission between them. Direct comparisons among all the multi-domain NRs studied crystallographically to date show significant variations within their quaternary architectures, rather than a common architecture adhering to strict rules. RXR remains flexible and adaptive by maintaining loosely organized domains, while its heterodimerization partners use a surface patch on their LBDs to form domain-domain interactions with DBDs.Nuclear receptors (NR) are multidomain proteins, which makes their crystallization challenging. Here the authors present the crystal structure of the retinoic acid receptor β-retinoic X receptor α (RARβ-RXRα) heterodimer bound to DNA, ligands and coactivator peptides, which shows that NR quaternary architectures are variable.
Using distinct classes of RARβ ligands, we asked if switching from the agonist REA to an antagonist BMS-18945321 produced effects outside the RARβ LBD (Fig. 2). H/D-ex MS studies were used to readily and accurately address this question, given the lack of success in crystallizing alternate complexes with different ligands or DNA. The deuteration level (indicated with the rainbow colors in Fig. 2a) of residues monitored by MS, correlates well with the flexibility of local structures. This technique can also identify conformational changes induced by different ligands or DNA when used in a comparative manner (i.e., subtraction of the deuteration levels of each residues in different conditions as shown with the blue-white-red heat maps in Fig. 2a). H/D-ex MS showed that helix-12, associated with the activation function-2, whose conformational and dynamic state is known to be highly responsive to ligand binding to RAR8, registered clear changes (increased deuteration level) when ligands were switched from agonist REA to antagonist BMS-189453 (Fig. 2a, b), indicating less stable conformation of this region due to the switch. Additionally, the DBD and hinge region of RARβ registered an altered H/D-ex MS pattern (increased deuteration level) when the DNA response element was switched from DR1 to DR5 (Fig. 2a), indicating these regions undergo conformational changes upon binding of DNAs with different spacers.
Understanding the precise molecular underpinnings of NR function requires the direct high-resolution visualization of multi-domain and functionally dimerized NRs bound to DNA and also with the constellation of transcriptional coregulators that interact upon a specific signal or stimulus. The ability to directly visualize these types of complexes for crystallographic studies has been largely hampered by abilities to generate the required full-length proteins in pure and stable forms, and the further difficulties in forming diffracting crystals when each of these proteins has large disordered regions within their polypeptides. Due to these limitations, the large majority of structural studies conducted over the past three decades for the NR family involved only isolated single domains; therefore, failing to reveal the complexities and variations of their quaternary architectures and the physical pathways for functional communications between domains. The current structure and the three previous co-crystal structures of NRs that used multi-domain proteins and dimeric complexes on DNA show that the overall quaternary states in this family are quite diverse and do not conform to a previous set of rules suggested from an interpretation of solution-based studies7. Moreover, the key interactions between LBDs and DBDs that are consistently seen crystallographically in four structures to date, were missing and incorrectly interpreted in a set of previously suggested models7 (Fig. 5).
We thank Z. Simandi and L. Nagy for the human RXRα expression and luciferase reporter plasmids, members of the Structural Biology Center at Argonne National Laboratory for their help with data collection at the 19-ID beamline. This work was supported by the National Institutes of Health grants (R01GM117013 and R01GM120532) to F.R., NIH grants (1U19AI117905, R01GM020501, R01AI101436) to S.L., and the Qilu Young Scholar funding from Shandong University (11200086963072) to D.W.
V.C. purified the proteins, carried out crystallization, and performed the biochemical assays. D.W. solved the structure, conducted cell-based experiments, and wrote the manuscript. S.L. performed the hydrogen/deuterium exchange mass spectrometry experiments. N.P. produced the expression and mutation constructs. Y.K. collected and processed synchrotron diffraction data. F.R. supervised the work and wrote the manuscript.
Retinoic acid receptors (RARs) and Retinoid X nuclear receptors (RXRs) are ligand-dependent transcriptional modulators that execute their biological action through the generation of functional heterodimers. RXR acts as an obligate dimer partner in many signalling pathways, gene regulation by rexinoids depending on the liganded state of the specific heterodimeric partner. To address the question of the effect of rexinoid antagonists on RAR/RXR function, we solved the crystal structure of the heterodimer formed by the ligand binding domain (LBD) of the RARα bound to its natural agonist ligand (all-trans retinoic acid, atRA) and RXRα bound to a rexinoid antagonist (LG100754). We observed that RARα exhibits the canonical agonist conformation and RXRα an antagonist one with the C-terminal H12 flipping out to the solvent. Examination of the protein-LG100754 interactions reveals that its propoxy group sterically prevents the H12 associating with the LBD, without affecting the dimerization or the active conformation of RAR. Although LG100754 has been reported to act as a 'phantom ligand' activating RAR in a cellular context, our structural data and biochemical assays demonstrate that LG100754 mediates its effect as a full RXR antagonist. Finally we show that the 'phantom ligand effect' of the LG100754 is due to a direct binding of the ligand to RAR that stabilizes coactivator interactions thus accounting for the observed transcriptional activation of RAR/RXR.
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So the researchers closely examined crystal structures of RAR-α, -β and -γ bound to retinoic acid, identifying structural differences in the ways the three receptors bind to their common ligand. With this information, they designed and synthesized approximately 100 compounds and evaluated their ability to selectively inhibit RAR-α in cells. They identified a compound, which was named YCT529, that inhibited RAR-α almost 500 times more potently than it did RAR-β and -γ. When given orally to male mice for 4 weeks, YCT529 dramatically reduced sperm counts and was 99% effective in preventing pregnancy, without any observable side effects. The mice could father pups again 4-6 weeks after they stopped receiving the compound. 2ff7e9595c
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