5m24

RARg mutant-S371E

spinqualitylabelsall models 5m24, resolution 1.69Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5m24 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.69Å Ligands: 9CR, CL, LMU Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function RARG_HUMAN Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, acts mainly as an activator of gene expression due to weak binding to corepressors. Required for limb bud development. In concert with RARA or RARB, required for skeletal growth, matrix homeostasis and growth plate function (By similarity). Publication Abstract from PubMed Retinoic acid (RA) plays key roles in cell differentiation and growth arrest through nuclear retinoic acid receptors (RARs), which are ligand-dependent transcription factors. While the main trigger of RAR activation is the binding of RA, phosphorylation of the receptors has also emerged as an important regulatory signal. Phosphorylation of the RARgamma N-terminal domain (NTD) is known to play a functional role in neuronal differentiation. In this work, we investigated the phosphorylation of RARgamma ligand binding domain (LBD), and present evidence that the phosphorylation status of the LBD affects the phosphorylation of the NTD region. We solved the X-ray structure of a phospho-mimetic mutant of the LBD (RARgamma S371E), which we used in molecular dynamics simulations to characterize the consequences of the S371E mutation on the RARgamma structural dynamics. Combined with simulations of the wild-type LBD, we show that the conformational equilibria of LBD salt bridges (notably R387-D340) are affected by the S371E mutation, which likely affects the recruitment of the kinase complex that phosphorylates the NTD. The molecular dynamics simulations also showed that a conservative mutation in this salt bridge (R387K) affects the dynamics of the LBD without inducing large conformational changes. Finally, cellular assays showed that the phosphorylation of the NTD of RARgamma is differentially regulated by retinoic acid in RARgammaWT and in the S371N, S371E and R387K mutants. This multidisciplinary work highlights an allosteric coupling between phosphorylations of the LBD and the NTD of RARgamma and supports the importance of structural dynamics involving electrostatic interactions in the regulation of RARs activity. Allosteric Regulation in the Ligand Binding Domain of Retinoic Acid Receptorgamma.,Chebaro Y, Sirigu S, Amal I, Lutzing R, Stote RH, Rochette-Egly C, Rochel N, Dejaegere A PLoS One. 2017 Jan 26;12(1):e0171043. doi: 10.1371/journal.pone.0171043., eCollection 2017. PMID:28125680 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Retinoic acid receptor 3D structures

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