4pld

From Proteopedia

(Difference between revisions)

Revision as of 08:42, 22 November 2017

Human Nuclear Receptor Liver Receptor Homologue-1, LRH-1, in its apo State Bound to a Fragment of Human TIF-2

Structural highlights

4pld is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	4ple
Gene:	NR5A2, B1F, CPF, FTF (HUMAN)
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

[NR5A2_HUMAN] Binds to the sequence element 5'-AACGACCGACCTTGAG-3' of the enhancer II of hepatitis B virus genes, a critical cis-element of their expression and regulation. May be responsible for the liver-specific activity of enhancer II, probably in combination with other hepatocyte transcription factors. Key regulator of cholesterol 7-alpha-hydroxylase gene (CYP7A) expression in liver. May also contribute to the regulation of pancreas-specific genes and play important roles in embryonic development. [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

Phospholipids (PLs) are unusual signaling hormones sensed by the nuclear receptor liver receptor homolog 1 (LRH 1), which has evolved a novel allosteric pathway to support appropriate interaction with coregulators depending on ligand status. LRH-1 plays an important role in controlling lipid and cholesterol homeostasis and is a potential target for the treatment of metabolic and neoplastic diseases. While the prospect of modulating LRH-1 via small molecules is exciting, the molecular mechanism linking PL structure to transcriptional coregulator preference is unknown. Previous studies showed that binding to an activating PL ligand, such as dilauroylphosphatidylcholine (DLPC), favors LRH-1s interaction with transcriptional coactivators to upregulate gene expression. Both crystallographic and solution based structural studies showed that DLPC binding drives unanticipated structural fluctuations outside of the canonical activation surface in an alternate activation function (AF) region, encompassing the beta-sheet-H6 region of the protein. However, the mechanism by which dynamics in the alternate AF influences coregulator selectivity remains elusive. Here we pair x-ray crystallography with molecular modeling to identify an unexpected allosteric network that traverses the protein ligand binding pocket and links these two elements to dictate selectivity. We show that communication between the alternate AF region and classical AF2 dictates the strength of the coregulator interaction. This work offers the first glimpse into the conformational dynamics that drive this unusual PL-mediated nuclear hormone receptor activation.

Unexpected Allosteric Network Contributes to LRH-1 Coregulator Selectivity.,Musille PM, Kossmann BR, Kohn JA, Ivanov I, Ortlund EA J Biol Chem. 2015 Nov 9. pii: jbc.M115.662874. PMID:26553876^[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
↑ Musille PM, Kossmann BR, Kohn JA, Ivanov I, Ortlund EA. Unexpected Allosteric Network Contributes to LRH-1 Coregulator Selectivity. J Biol Chem. 2015 Nov 9. pii: jbc.M115.662874. PMID:26553876 doi:http://dx.doi.org/10.1074/jbc.M115.662874

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4pld"

@@ Line 1: / Line 1: @@
 ==Human Nuclear Receptor Liver Receptor Homologue-1, LRH-1, in its apo State Bound to a Fragment of Human TIF-2==
 <StructureSection load='4pld' size='340' side='right' caption='[[4pld]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4pld]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PLD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4PLD FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4pld]] is a 2 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=4PLD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4PLD FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CPS:3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE'>CPS</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ple|4ple]]</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=4pld FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pld OCA], [http://pdbe.org/4pld PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4pld RCSB], [http://www.ebi.ac.uk/pdbsum/4pld PDBsum]</span></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NR5A2, B1F, CPF, FTF ([http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4pld FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pld OCA], [http://pdbe.org/4pld PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4pld RCSB], [http://www.ebi.ac.uk/pdbsum/4pld PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4pld ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 24: / Line 26: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Musille, P M]]
 [[Category: Ortlund, E A]]

4pld

From Proteopedia

Revision as of 08:42, 22 November 2017

Human Nuclear Receptor Liver Receptor Homologue-1, LRH-1, in its apo State Bound to a Fragment of Human TIF-2

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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