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{{STRUCTURE_3lqh| PDB=3lqh |  SCENE=  }}
==Crystal structure of MLL1 PHD3-Bromo in the free form==
===Crystal structure of MLL1 PHD3-Bromo in the free form===
<StructureSection load='3lqh' size='340' side='right' caption='[[3lqh]], [[Resolution|resolution]] 1.72&Aring;' scene=''>
{{ABSTRACT_PUBMED_20541251}}
== Structural highlights ==
<table><tr><td colspan='2'>[[3lqh]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3LQH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3LQH FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3lqi|3lqi]], [[3lqj|3lqj]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MLL, ALL1, CXXC7, HRX, HTRX, KMT2A, MLL1, TRX1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone-lysine_N-methyltransferase Histone-lysine N-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.43 2.1.1.43] </span></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=3lqh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3lqh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3lqh RCSB], [http://www.ebi.ac.uk/pdbsum/3lqh PDBsum]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/MLL1_HUMAN MLL1_HUMAN]] Defects in MLL are the cause of Wiedemann-Steiner syndrome (WDSTS) [MIM:[http://omim.org/entry/605130 605130]]. A syndrome characterized by hairy elbows (hypertrichosis cubiti), intellectual disability, a distinctive facial appearance, and short stature. Facial characteristics include long eyelashes, thick or arched eyebrows with a lateral flare, and downslanting and vertically narrow palpebral fissures.<ref>PMID:10490642</ref> <ref>PMID:22795537</ref>  Note=Chromosomal aberrations involving MLL are a cause of acute leukemias. Translocation t(1;11)(q21;q23) with MLLT11/AF1Q; translocation t(3;11)(p21;q23) with NCKIPSD/AF3p21; translocation t(3,11)(q25,q23) with GMPS; translocation t(4;11)(q21;q23) with AFF1/MLLT2/AF4; insertion ins(5;11)(q31;q13q23) with AFF4/AF5Q31; translocation t(5;11)(q12;q23) with AF5-alpha/CENPK; translocation t(6;11)(q27;q23) with MLLT4/AF6; translocation t(9;11)(p22;q23) with MLLT3/AF9; translocation t(10;11)(p11.2;q23) with ABI1; translocation t(10;11)(p12;q23) with MLLT10/AF10; t(11;15)(q23;q14) with CASC5 and ZFYVE19; translocation t(11;17)(q23;q21) with MLLT6/AF17; translocation t(11;19)(q23;p13.3) with ELL; translocation t(11;19)(q23;p13.3) with MLLT1/ENL; translocation t(11;19)(q23;p23) with GAS7; translocation t(X;11)(q13;q23) with FOXO4/AFX1. Translocation t(3;11)(q28;q23) with LPP. Translocation t(10;11)(q22;q23) with TET1. Translocation t(9;11)(q34;q23) with DAB2IP. Translocation t(4;11)(p12;q23) with FRYL. Fusion proteins MLL-MLLT1, MLL-MLLT3 and MLL-ELL interact with PPP1R15A and, on the contrary to unfused MLL, inhibit PPP1R15A-induced apoptosis.<ref>PMID:10490642</ref>  Note=A chromosomal aberration involving MLL may be a cause of chronic neutrophilic leukemia. Translocation t(4;11)(q21;q23) with SEPT11.<ref>PMID:10490642</ref>  
== Function ==
[[http://www.uniprot.org/uniprot/MLL1_HUMAN MLL1_HUMAN]] Histone methyltransferase that plays an essential role in early development and hematopoiesis. Catalytic subunit of the MLL1/MLL complex, a multiprotein complex that mediates both methylation of 'Lys-4' of histone H3 (H3K4me) complex and acetylation of 'Lys-16' of histone H4 (H4K16ac). In the MLL1/MLL complex, it specifically mediates H3K4me, a specific tag for epigenetic transcriptional activation. Has weak methyltransferase activity by itself, and requires other component of the MLL1/MLL complex to obtain full methyltransferase activity. Has no activity toward histone H3 phosphorylated on 'Thr-3', less activity toward H3 dimethylated on 'Arg-8' or 'Lys-9', while it has higher activity toward H3 acetylated on 'Lys-9'. Required for transcriptional activation of HOXA9. Promotes PPP1R15A-induced apoptosis.<ref>PMID:10490642</ref> <ref>PMID:12453419</ref> <ref>PMID:15960975</ref> <ref>PMID:19556245</ref>  
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/lq/3lqh_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The MLL1 gene is a frequent target for recurrent chromosomal translocations, resulting in transformation of hematopoietic precursors into leukemia stem cells. Here, we report on structure-function studies that elucidate molecular events in MLL1 binding of histone H3K4me3/2 marks and recruitment of the cyclophilin CyP33. CyP33 contains a PPIase and a RRM domain and regulates MLL1 function through HDAC recruitment. We find that the PPIase domain of CyP33 regulates the conformation of MLL1 through proline isomerization within the PHD3-Bromo linker, thereby disrupting the PHD3-Bromo interface and facilitating binding of the MLL1-PHD3 domain to the CyP33-RRM domain. H3K4me3/2 and CyP33-RRM target different surfaces of MLL1-PHD3 and can bind simultaneously to form a ternary complex. Furthermore, the MLL1-CyP33 interaction is required for repression of HOXA9 and HOXC8 genes in vivo. Our results highlight the role of PHD3-Bromo cassette as a regulatory platform, orchestrating MLL1 binding of H3K4me3/2 marks and cyclophilin-mediated repression through HDAC recruitment.


==Disease==
Pro isomerization in MLL1 PHD3-bromo cassette connects H3K4me readout to CyP33 and HDAC-mediated repression.,Wang Z, Song J, Milne TA, Wang GG, Li H, Allis CD, Patel DJ Cell. 2010 Jun 25;141(7):1183-94. Epub 2010 Jun 10. PMID:20541251<ref>PMID:20541251</ref>
[[http://www.uniprot.org/uniprot/MLL1_HUMAN MLL1_HUMAN]] Defects in MLL are the cause of Wiedemann-Steiner syndrome (WDSTS) [MIM:[http://omim.org/entry/605130 605130]]. A syndrome characterized by hairy elbows (hypertrichosis cubiti), intellectual disability, a distinctive facial appearance, and short stature. Facial characteristics include long eyelashes, thick or arched eyebrows with a lateral flare, and downslanting and vertically narrow palpebral fissures.<ref>PMID:10490642</ref><ref>PMID:22795537</ref>  Note=Chromosomal aberrations involving MLL are a cause of acute leukemias. Translocation t(1;11)(q21;q23) with MLLT11/AF1Q; translocation t(3;11)(p21;q23) with NCKIPSD/AF3p21; translocation t(3,11)(q25,q23) with GMPS; translocation t(4;11)(q21;q23) with AFF1/MLLT2/AF4; insertion ins(5;11)(q31;q13q23) with AFF4/AF5Q31; translocation t(5;11)(q12;q23) with AF5-alpha/CENPK; translocation t(6;11)(q27;q23) with MLLT4/AF6; translocation t(9;11)(p22;q23) with MLLT3/AF9; translocation t(10;11)(p11.2;q23) with ABI1; translocation t(10;11)(p12;q23) with MLLT10/AF10; t(11;15)(q23;q14) with CASC5 and ZFYVE19; translocation t(11;17)(q23;q21) with MLLT6/AF17; translocation t(11;19)(q23;p13.3) with ELL; translocation t(11;19)(q23;p13.3) with MLLT1/ENL; translocation t(11;19)(q23;p23) with GAS7; translocation t(X;11)(q13;q23) with FOXO4/AFX1. Translocation t(3;11)(q28;q23) with LPP. Translocation t(10;11)(q22;q23) with TET1. Translocation t(9;11)(q34;q23) with DAB2IP. Translocation t(4;11)(p12;q23) with FRYL. Fusion proteins MLL-MLLT1, MLL-MLLT3 and MLL-ELL interact with PPP1R15A and, on the contrary to unfused MLL, inhibit PPP1R15A-induced apoptosis.<ref>PMID:10490642</ref>  Note=A chromosomal aberration involving MLL may be a cause of chronic neutrophilic leukemia. Translocation t(4;11)(q21;q23) with SEPT11.<ref>PMID:10490642</ref>  


==Function==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[http://www.uniprot.org/uniprot/MLL1_HUMAN MLL1_HUMAN]] Histone methyltransferase that plays an essential role in early development and hematopoiesis. Catalytic subunit of the MLL1/MLL complex, a multiprotein complex that mediates both methylation of 'Lys-4' of histone H3 (H3K4me) complex and acetylation of 'Lys-16' of histone H4 (H4K16ac). In the MLL1/MLL complex, it specifically mediates H3K4me, a specific tag for epigenetic transcriptional activation. Has weak methyltransferase activity by itself, and requires other component of the MLL1/MLL complex to obtain full methyltransferase activity. Has no activity toward histone H3 phosphorylated on 'Thr-3', less activity toward H3 dimethylated on 'Arg-8' or 'Lys-9', while it has higher activity toward H3 acetylated on 'Lys-9'. Required for transcriptional activation of HOXA9. Promotes PPP1R15A-induced apoptosis.<ref>PMID:10490642</ref><ref>PMID:12453419</ref><ref>PMID:15960975</ref><ref>PMID:19556245</ref>  
</div>


==About this Structure==
==See Also==
[[3lqh]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3LQH OCA].
*[[Histone methyltransferase|Histone methyltransferase]]
 
== References ==
==Reference==
<references/>
<ref group="xtra">PMID:020541251</ref><references group="xtra"/><references/>
__TOC__
</StructureSection>
[[Category: Histone-lysine N-methyltransferase]]
[[Category: Histone-lysine N-methyltransferase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Patel, D J.]]
[[Category: Patel, D J]]
[[Category: Wang, Z.]]
[[Category: Wang, Z]]
[[Category: Apoptosis]]
[[Category: Apoptosis]]
[[Category: Bromodomain]]
[[Category: Bromodomain]]

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