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5mk4

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Revision as of 07:21, 19 August 2020

Crystal structure of the Retinoid X Receptor alpha in complex with synthetic honokiol derivative 7 and a fragment of the TIF2 co-activator.

Structural highlights

5mk4 is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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

[RXRA_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. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR 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, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes.^[1] ^[2] ^[3] ^[4] [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.^[5]

Publication Abstract from PubMed

Retinoid X receptors (RXRs) play key roles in many physiological processes in both the periphery and central nervous system. In addition, RXRs form heterodimers with other nuclear receptors to exert their physiological effects. The nuclear receptor related 1 protein (NURR1) is particularly interesting because of its role in promoting differentiation and survival of dopamine neurons. However, only a small number of RXR-heterodimer selective modulators are available, with limited chemical diversity. This work describes the synthesis, biochemical evaluation, and structural elucidation of a novel series of RXR ligands with strongly biased interactions with RXRalpha-NURR1 heterodimers. Targeted modifications to the small molecule biaryl scaffold caused local RXRalpha side-chain disturbances and displacement of secondary structural elements upon ligand binding. This resulted in the repositioning of protein helices in the heterodimer interface of RXRalpha, alterations in homo- versus heterodimer formation, and modulation of activation function 2 (AF2). The data provide a rationale for the design of RXR ligands consisting of a highly conserved hydrophilic region, strongly contributing to the ligand affinity, and a variable hydrophobic region, which efficiently probes the effects of structural changes at the level of the ligand on co-regulator recruitment or the RXRalpha-NURR1 dimerization interface.

Ligand Dependent Switch from RXR Homo- to RXR-NURR1 Heterodimerization.,Scheepstra M, Andrei SA, de Vries RMJM, Meijer FA, Ma JN, Burstein ES, Olsson R, Ottmann C, Milroy LG, Brunsveld L ACS Chem Neurosci. 2017 Sep 20;8(9):2065-2077. doi: 10.1021/acschemneuro.7b00216., Epub 2017 Jul 24. PMID:28691794^[6]

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

References

↑ Gorla-Bajszczak A, Juge-Aubry C, Pernin A, Burger AG, Meier CA. Conserved amino acids in the ligand-binding and tau(i) domains of the peroxisome proliferator-activated receptor alpha are necessary for heterodimerization with RXR. Mol Cell Endocrinol. 1999 Jan 25;147(1-2):37-47. PMID:10195690
↑ Harish S, Ashok MS, Khanam T, Rangarajan PN. Serine 27, a human retinoid X receptor alpha residue, phosphorylated by protein kinase A is essential for cyclicAMP-mediated downregulation of RXRalpha function. Biochem Biophys Res Commun. 2000 Dec 29;279(3):853-7. PMID:11162439 doi:10.1006/bbrc.2000.4043
↑ Tsutsumi T, Suzuki T, Shimoike T, Suzuki R, Moriya K, Shintani Y, Fujie H, Matsuura Y, Koike K, Miyamura T. Interaction of hepatitis C virus core protein with retinoid X receptor alpha modulates its transcriptional activity. Hepatology. 2002 Apr;35(4):937-46. PMID:11915042 doi:10.1053/jhep.2002.32470
↑ Santos NC, Kim KH. Activity of retinoic acid receptor-alpha is directly regulated at its protein kinase A sites in response to follicle-stimulating hormone signaling. Endocrinology. 2010 May;151(5):2361-72. doi: 10.1210/en.2009-1338. Epub 2010 Mar , 9. PMID:20215566 doi:10.1210/en.2009-1338
↑ 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
↑ Scheepstra M, Andrei SA, de Vries RMJM, Meijer FA, Ma JN, Burstein ES, Olsson R, Ottmann C, Milroy LG, Brunsveld L. Ligand Dependent Switch from RXR Homo- to RXR-NURR1 Heterodimerization. ACS Chem Neurosci. 2017 Sep 20;8(9):2065-2077. doi: 10.1021/acschemneuro.7b00216., Epub 2017 Jul 24. PMID:28691794 doi:http://dx.doi.org/10.1021/acschemneuro.7b00216

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/5mk4"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the Retinoid X Receptor alpha in complex with synthetic honokiol derivative 7 and a fragment of the TIF2 co-activator.==
-<StructureSection load='5mk4' size='340' side='right' caption='[[5mk4]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+<StructureSection load='5mk4' size='340' side='right'caption='[[5mk4]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5mk4]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MK4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MK4 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5mk4]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MK4 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5MK4 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=I5W:(~{E})-3-[3-(2-methyl-5-phenyl-phenyl)-4-oxidanyl-phenyl]prop-2-enoic+acid'>I5W</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=I5W:(~{E})-3-[3-(2-methyl-5-phenyl-phenyl)-4-oxidanyl-phenyl]prop-2-enoic+acid'>I5W</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5mk4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mk4 OCA], [http://pdbe.org/5mk4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mk4 RCSB], [http://www.ebi.ac.uk/pdbsum/5mk4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mk4 ProSAT]</span></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=5mk4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mk4 OCA], [http://pdbe.org/5mk4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mk4 RCSB], [http://www.ebi.ac.uk/pdbsum/5mk4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mk4 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 20: / Line 20: @@
 </div>
 <div class="pdbe-citations 5mk4" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Retinoid X receptor 3D structures|Retinoid X receptor 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Andrei, S A]]
 [[Category: Brunsveld, L]]

5mk4

From Proteopedia

Revision as of 07:21, 19 August 2020

Crystal structure of the Retinoid X Receptor alpha in complex with synthetic honokiol derivative 7 and a fragment of the TIF2 co-activator.

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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