5dx3: Difference between revisions

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-'''Unreleased structure'''
-The entry 5dx3 is ON HOLD  until Paper Publication
+==Estrogen Receptor Alpha Ligand Binding Domain Y537S Mutant in Complex with Stapled Peptide SRC2-P3 and Estradiol==
+<StructureSection load='5dx3' size='340' side='right' caption='[[5dx3]], [[Resolution|resolution]] 2.09&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5dx3]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DX3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5DX3 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=EST:ESTRADIOL'>EST</scene></td></tr>
+<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=5GM:(4S)-2,4-DIMETHYL-L-NORLEUCINE'>5GM</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=MK8:2-METHYL-L-NORLEUCINE'>MK8</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</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=5dx3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dx3 OCA], [http://pdbe.org/5dx3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dx3 RCSB], [http://www.ebi.ac.uk/pdbsum/5dx3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5dx3 ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[[http://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/ESR1_HUMAN ESR1_HUMAN]] Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Isoform 3 can bind to ERE and inhibit isoform 1.<ref>PMID:7651415</ref> <ref>PMID:10970861</ref> <ref>PMID:9328340</ref> <ref>PMID:10681512</ref> <ref>PMID:10816575</ref> <ref>PMID:11477071</ref> <ref>PMID:11682626</ref> <ref>PMID:15078875</ref> <ref>PMID:16043358</ref> <ref>PMID:15891768</ref> <ref>PMID:16684779</ref> <ref>PMID:18247370</ref> <ref>PMID:17932106</ref> <ref>PMID:19350539</ref> <ref>PMID:20705611</ref> <ref>PMID:21937726</ref> <ref>PMID:21330404</ref> <ref>PMID:22083956</ref>  [[http://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 ==
+"Stapled" peptides are typically designed to replace two non-interacting residues with a constraining, olefinic staple. To mimic interacting leucine and isoleucine residues, we have created new amino acids that incorporate a methyl group in the gamma-position of the stapling amino acid S5. We have incorporated them into a sequence derived from steroid receptor coactivator 2, which interacts with estrogen receptor alpha. The best peptide (IC50 =89 nm) replaces isoleucine 689 with an S-gamma-methyl stapled amino acid, and has significantly higher affinity than unsubstituted peptides (390 and 760 nm). Through X-ray crystallography and molecular dynamics studies, we show that the conformation taken up by the S-gamma-methyl peptide minimizes the syn-pentane interactions between the alpha- and gamma-methyl groups.
-Authors: Speltz, T.E., Fanning, S.W., Mayne, C.G., Tajkhorshid, E., Greene, G.L., Moore, T.W.
+Stapled Peptides with gamma-Methylated Hydrocarbon Chains for the Estrogen Receptor/Coactivator Interaction.,Speltz TE, Fanning SW, Mayne CG, Fowler C, Tajkhorshid E, Greene GL, Moore TW Angew Chem Int Ed Engl. 2016 Mar 18;55(13):4252-5. doi: 10.1002/anie.201510557., Epub 2016 Mar 1. PMID:26928945<ref>PMID:26928945</ref>
-Description: Estrogen Receptor Alpha Ligand Binding Domain Y537S Mutant in Complex with Stapled Peptide SRC2-P3 and Estradiol
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Moore, T.W]]
+<div class="pdbe-citations 5dx3" style="background-color:#fffaf0;"></div>
-[[Category: Greene, G.L]]
+== References ==
-[[Category: Speltz, T.E]]
+<references/>
-[[Category: Fanning, S.W]]
+__TOC__
-[[Category: Mayne, C.G]]
+</StructureSection>
+[[Category: Fanning, S W]]
+[[Category: Greene, G L]]
+[[Category: Mayne, C G]]
+[[Category: Moore, T W]]
+[[Category: Speltz, T E]]
 [[Category: Tajkhorshid, E]]
+[[Category: Af-2 binding]]
+[[Category: Estrogen receptor alpha]]
+[[Category: Hormone receptor-peptide complex]]
+[[Category: Peptide mimetic]]
+[[Category: Somatic mutation]]
+[[Category: Stapled peptide]]
+[[Category: Synthetic peptide]]