5i4v
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Discovery of novel, orally efficacious Liver X Receptor (LXR) beta agonists== | |
| + | <StructureSection load='5i4v' size='340' side='right'caption='[[5i4v]], [[Resolution|resolution]] 2.61Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5i4v]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5I4V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5I4V FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.61Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=67S:{2-[(2R)-4-[4-(HYDROXYMETHYL)-3-(METHYLSULFONYL)PHENYL]-2-(PROPAN-2-YL)PIPERAZIN-1-YL]-4-(TRIFLUOROMETHYL)PYRIMIDIN-5-YL}METHANOL'>67S</scene></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5i4v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i4v OCA], [https://pdbe.org/5i4v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5i4v RCSB], [https://www.ebi.ac.uk/pdbsum/5i4v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5i4v ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/NCOA2_HUMAN 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 == | ||
| + | [https://www.uniprot.org/uniprot/NR1H2_HUMAN NR1H2_HUMAN] Orphan receptor. Binds preferentially to double-stranded oligonucleotide direct repeats having the consensus half-site sequence 5'-AGGTCA-3' and 4-nt spacing (DR-4). Regulates cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8 (By similarity).[https://www.uniprot.org/uniprot/NCOA2_HUMAN 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.<ref>PMID:9430642</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | This article describes the application of Contour to the design and discovery of a novel, potent, orally efficacious liver X receptor beta (LXRbeta) agonist (17). Contour technology is a structure-based drug design platform that generates molecules using a context perceptive growth algorithm guided by a contact sensitive scoring function. The growth engine uses binding site perception and programmable growth capability to create drug-like molecules by assembling fragments that naturally complement hydrophilic and hydrophobic features of the protein binding site. Starting with a crystal structure of LXRbeta and a docked 2-(methylsulfonyl)benzyl alcohol fragment (6), Contour was used to design agonists containing a piperazine core. Compound 17 binds to LXRbeta with high affinity and to LXRalpha to a lesser extent, and induces the expression of LXR target genes in vitro and in vivo. This molecule served as a starting point for further optimization and generation of a candidate which is currently in human clinical trials for treating atopic dermatitis. | ||
| - | + | Discovery of a Novel, Orally Efficacious Liver X Receptor (LXR) beta Agonist.,Zheng Y, Zhuang L, Fan KY, Tice CM, Zhao W, Dong C, Lotesta SD, Leftheris K, Lindblom PR, Liu Z, Shimada J, Noto PB, Meng S, Hardy A, Howard L, Krosky P, Guo J, Lipinski K, Kandpal G, Bukhtiyarov Y, Zhao Y, Lala D, Van Orden R, Zhou J, Chen G, Wu Z, McKeever BM, McGeehan GM, Gregg RE, Claremon DA, Singh SB J Med Chem. 2016 Apr 14;59(7):3264-71. doi: 10.1021/acs.jmedchem.5b02029. Epub, 2016 Mar 29. PMID:26990539<ref>PMID:26990539</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 5i4v" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Liver X receptor|Liver X receptor]] | ||
| + | *[[Retinoid X receptor 3D structures|Retinoid X receptor 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Chen G]] | ||
| + | [[Category: McKeever BM]] | ||
Current revision
Discovery of novel, orally efficacious Liver X Receptor (LXR) beta agonists
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