3oap: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Crystal structure of human Retinoid X Receptor alpha-ligand binding domain complex with 9-cis retinoic acid and the coactivator peptide GRIP-1== | ==Crystal structure of human Retinoid X Receptor alpha-ligand binding domain complex with 9-cis retinoic acid and the coactivator peptide GRIP-1== | ||
<StructureSection load='3oap' size='340' side='right' caption='[[3oap]], [[Resolution|resolution]] 2.05Å' scene=''> | <StructureSection load='3oap' size='340' side='right'caption='[[3oap]], [[Resolution|resolution]] 2.05Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3oap]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3oap]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3OAP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3OAP FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9CR:(9CIS)-RETINOIC+ACID'>9CR</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9CR:(9CIS)-RETINOIC+ACID'>9CR</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1fby|1fby]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1fby|1fby]]</div></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RXRA, NR2B1 ([ | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RXRA, NR2B1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3oap FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3oap OCA], [https://pdbe.org/3oap PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3oap RCSB], [https://www.ebi.ac.uk/pdbsum/3oap PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3oap ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == 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 == | == Function == | ||
[[ | [[https://www.uniprot.org/uniprot/RXRA_HUMAN 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.<ref>PMID:10195690</ref> <ref>PMID:11162439</ref> <ref>PMID:11915042</ref> <ref>PMID:20215566</ref> [[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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 22: | Line 22: | ||
</div> | </div> | ||
<div class="pdbe-citations 3oap" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 3oap" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Retinoid X receptor 3D structures|Retinoid X receptor 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
| Line 27: | Line 30: | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | [[Category: Human]] | ||
[[Category: Large Structures]] | |||
[[Category: Muccio, D D]] | [[Category: Muccio, D D]] | ||
[[Category: Smith, C D]] | [[Category: Smith, C D]] | ||
Revision as of 10:19, 12 May 2022
Crystal structure of human Retinoid X Receptor alpha-ligand binding domain complex with 9-cis retinoic acid and the coactivator peptide GRIP-1Crystal structure of human Retinoid X Receptor alpha-ligand binding domain complex with 9-cis retinoic acid and the coactivator peptide GRIP-1
Structural highlights
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 PubMedRetinoid X receptors (RXRs) are ligand-dependent nuclear receptors, which are activated by the potent agonist 9-cis retinoic acid (9cRA). 9cRA binds to the ligand binding domain (LBD) of RXRs, and recruits coactivator proteins for gene transcription. Using isothermal titration calorimetry, the binding of a 13-mer coactivator peptide, GRIP-1, to the hRXRalpha-LBD homodimer complex containing 9cRA (hRXRalpha-LBD:9cRA:GRIP-1) is reported between 20 degrees and 37 degrees C. DeltaG is temperature independent (-8.5 kcal/mol), and GRIP-1 binding is driven by DeltaH (-9.2 kcal/mol) at 25 degrees C. DeltaCp is large and negative (-401 cal/mol-K). The crystal structure of hRXRalpha-LBD:9cRA:GRIP-1 is reported at 2.05 A. When the structures of hRXRalpha-LBD:9cRA:GRIP-1 and hRXRalpha-LBD:9cRA (1FBY) homodimers are compared, E453 and E456 on helix 12 bury and form ionic interactions with GRIP-1. R302 on helix 4 realigns to form new salt bridges to both E453 and E456. F277 (helix 3), F437 (helix 11), and F450 (helix 12) move toward the hydrophobic interior. The changes in the near-UV spectrum at 260 nm of the hRXRalpha-LBD:9cRA:GRIP-1 support this structural change. Helix 11 tilts toward helix 12 by approximately 1 A modifying the ring conformation of 9cRA. Hydrogen-deuterium exchange mass spectroscopy indicate GRIP-1 binding to hRXRalpha-LBD:9cRA significantly decreases the exchange rates for peptides containing helices 3 (F277), 4 (R302), 11 (F437) and 12 (E453; E456). The structural changes and loss of dynamics of the GRIP-1 bound structure are used to interpret the energetics of coactivator peptide binding to the agonist-bound hRXRalpha-LBD. Structure, Energetics and Dynamics of Binding Coactivator Peptide to Human Retinoid X Receptor Alpha Ligand Binding Domain Complex with 9-cis-Retinoic Acid.,Xia G, Boerma LJ, Cox BD, Qiu C, Kang S, Smith CD, Renfrow MB, Muccio DD Biochemistry. 2010 Nov 4. PMID:21049972[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||||