4pp3 | pdb_00004pp3

Crystal structure of human Retinoid X Receptor alpha-ligand binding domain complex with 6-methyl UAB30 and the coactivator peptide GRIP-1

spinqualitylabelsall models 4pp3, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4pp3 is a 2 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 2Å Ligands: 2VZ Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease NCOA2_HUMAN Note=Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation. Function NCOA2_HUMAN Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues. Publication Abstract from PubMed (2E,4E,6Z,8E)-8-(3',4'-Dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6- octatrienoic acid, 9cUAB30, is a selective rexinoid that displays substantial chemopreventive capacity with little toxicity. 4-Methyl-UAB30, an analogue of 9cUAB30, is a potent RXR agonist but caused increased lipid biosynthesis unlike 9cUAB30. To evaluate how methyl substitution influenced potency and lipid biosynthesis, we synthesized four 9cUAB30 homologues with methyl substitutions at the 5-, 6-, 7-, or 8-position of the tetralone ring. The syntheses and biological evaluations of these new analogues are reported here along with the X-ray crystal structures of each homologue bound to the ligand binding domain of hRXRalpha. We demonstrate that each homologue of 9cUAB30 is a more potent agonist, but only the 7-methyl-9cUAB30 caused severe hyperlipidemia in rats. On the basis of the X-ray crystal structures of these new rexinoids and bexarotene (Targretin) bound to hRXRalpha-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD. Methyl Substitution of a Rexinoid Agonist Improves Potency and Reveals Site of Lipid Toxicity.,Atigadda VR, Xia G, Desphande A, Boerma LJ, Lobo-Ruppert S, Grubbs CJ, Smith CD, Brouillette WJ, Muccio DD J Med Chem. 2014 Jun 5. PMID:24801499 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Retinoid X receptor 3D structures

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