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5i4v

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Discovery of novel, orally efficacious Liver X Receptor (LXR) beta agonists

Structural highlights

5i4v is a 4 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 2.61Å
Ligands:
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

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).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.^[1]

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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Voegel JJ, Heine MJ, Tini M, Vivat V, Chambon P, Gronemeyer H. The coactivator TIF2 contains three nuclear receptor-binding motifs and mediates transactivation through CBP binding-dependent and -independent pathways. EMBO J. 1998 Jan 15;17(2):507-19. PMID:9430642 doi:10.1093/emboj/17.2.507
↑ 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. Discovery of a Novel, Orally Efficacious Liver X Receptor (LXR) beta Agonist. J Med Chem. 2016 Apr 14;59(7):3264-71. doi: 10.1021/acs.jmedchem.5b02029. Epub, 2016 Mar 29. PMID:26990539 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b02029

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5i4v"

Categories: Homo sapiens | Large Structures | Chen G | McKeever BM

@@ Line 3: / Line 3: @@
 <StructureSection load='5i4v' size='340' side='right'caption='[[5i4v]], [[Resolution|resolution]] 2.61&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5i4v]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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 [http://proteopedia.org/fgij/fg.htm?mol=5I4V FirstGlance]. <br>
+<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='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>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.61&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NCOA2, BHLHE75, SRC2, TIF2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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'>[http://proteopedia.org/fgij/fg.htm?mol=5i4v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i4v OCA], [http://pdbe.org/5i4v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5i4v RCSB], [http://www.ebi.ac.uk/pdbsum/5i4v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5i4v ProSAT]</span></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 ==
-[[http://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). [[http://www.uniprot.org/uniprot/RXRB_HUMAN RXRB_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 (By similarity). Specifically binds 9-cis retinoic acid (9C-RA).
+[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 ==
@@ Line 27: / Line 29: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Chen, G]]
+[[Category: Chen G]]
-[[Category: McKeever, B M]]
+[[Category: McKeever BM]]
-[[Category: Agonist]]
-[[Category: Dna binding protein]]
-[[Category: Heterodimer]]
-[[Category: Lxrbeta-lbd]]
-[[Category: Rxrbeta-lbd]]

5i4v

From Proteopedia

Current revision

Discovery of novel, orally efficacious Liver X Receptor (LXR) beta agonists

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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