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| | <StructureSection load='6t1j' size='340' side='right'caption='[[6t1j]], [[Resolution|resolution]] 1.97Å' scene=''> | | <StructureSection load='6t1j' size='340' side='right'caption='[[6t1j]], [[Resolution|resolution]] 1.97Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6t1j]] is a 1 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=6T1J OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6T1J FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6t1j]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6T1J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6T1J FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=M7T:~{N}-[[4-(pyrrolidin-1-ylmethyl)phenyl]methyl]-4-thiophen-2-ylcarbonyl-piperazine-1-carboxamide'>M7T</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.97Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MLLT1, ENL, LTG19, YEATS1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=M7T:~{N}-[[4-(pyrrolidin-1-ylmethyl)phenyl]methyl]-4-thiophen-2-ylcarbonyl-piperazine-1-carboxamide'>M7T</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=6t1j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6t1j OCA], [http://pdbe.org/6t1j PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6t1j RCSB], [http://www.ebi.ac.uk/pdbsum/6t1j PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6t1j ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6t1j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6t1j OCA], [https://pdbe.org/6t1j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6t1j RCSB], [https://www.ebi.ac.uk/pdbsum/6t1j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6t1j ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/ENL_HUMAN ENL_HUMAN]] A chromosomal aberration involving MLLT1 is associated with acute leukemias. Translocation t(11;19)(q23;p13.3) with KMT2A/MLL1. The result is a rogue activator protein. | + | [https://www.uniprot.org/uniprot/ENL_HUMAN ENL_HUMAN] A chromosomal aberration involving MLLT1 is associated with acute leukemias. Translocation t(11;19)(q23;p13.3) with KMT2A/MLL1. The result is a rogue activator protein. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ENL_HUMAN ENL_HUMAN]] Component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA.<ref>PMID:20159561</ref> <ref>PMID:20471948</ref> | + | [https://www.uniprot.org/uniprot/ENL_HUMAN ENL_HUMAN] Component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA.<ref>PMID:20159561</ref> <ref>PMID:20471948</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Arrowsmith, C H]] | + | [[Category: Arrowsmith CH]] |
| - | [[Category: Bountra, C]] | + | [[Category: Bountra C]] |
| - | [[Category: Chaikuad, A]] | + | [[Category: Chaikuad A]] |
| - | [[Category: Edwards, A M]] | + | [[Category: Edwards AM]] |
| - | [[Category: Fedorov, O]] | + | [[Category: Fedorov O]] |
| - | [[Category: Heidenreich, D]] | + | [[Category: Heidenreich D]] |
| - | [[Category: Knapp, S]] | + | [[Category: Knapp S]] |
| - | [[Category: Structural genomic]]
| + | |
| - | [[Category: Chemical probe]]
| + | |
| - | [[Category: Enl]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Mllt1]]
| + | |
| - | [[Category: Sgc]]
| + | |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Yeats domain]]
| + | |
| Structural highlights
Disease
ENL_HUMAN A chromosomal aberration involving MLLT1 is associated with acute leukemias. Translocation t(11;19)(q23;p13.3) with KMT2A/MLL1. The result is a rogue activator protein.
Function
ENL_HUMAN Component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA.[1] [2]
Publication Abstract from PubMed
YEATS-domain-containing MLLT1 is an acetyl/acyl-lysine reader domain, which is structurally distinct from well-studied bromodomains and has been strongly associated in development of cancer. Here, we characterized piperazine-urea derivatives as an acetyl/acyl-lysine mimetic moiety for MLLT1. Crystal structures revealed distinct interaction mechanisms of this chemotype compared to the recently described benzimidazole-amide based inhibitors, exploiting different binding pockets within the protein. Thus, the piperazine-urea scaffold offers an alternative strategy for targeting the YEATS domain family.
Structural Insights into Interaction Mechanisms of Alternative Piperazine-urea YEATS Domain Binders in MLLT1.,Ni X, Heidenreich D, Christott T, Bennett J, Moustakim M, Brennan PE, Fedorov O, Knapp S, Chaikuad A ACS Med Chem Lett. 2019 Nov 25;10(12):1661-1666. doi:, 10.1021/acsmedchemlett.9b00460. eCollection 2019 Dec 12. PMID:31857843[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lin C, Smith ER, Takahashi H, Lai KC, Martin-Brown S, Florens L, Washburn MP, Conaway JW, Conaway RC, Shilatifard A. AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol Cell. 2010 Feb 12;37(3):429-37. doi: 10.1016/j.molcel.2010.01.026. PMID:20159561 doi:10.1016/j.molcel.2010.01.026
- ↑ He N, Liu M, Hsu J, Xue Y, Chou S, Burlingame A, Krogan NJ, Alber T, Zhou Q. HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Mol Cell. 2010 May 14;38(3):428-38. doi: 10.1016/j.molcel.2010.04.013. PMID:20471948 doi:10.1016/j.molcel.2010.04.013
- ↑ Ni X, Heidenreich D, Christott T, Bennett J, Moustakim M, Brennan PE, Fedorov O, Knapp S, Chaikuad A. Structural Insights into Interaction Mechanisms of Alternative Piperazine-urea YEATS Domain Binders in MLLT1. ACS Med Chem Lett. 2019 Nov 25;10(12):1661-1666. doi:, 10.1021/acsmedchemlett.9b00460. eCollection 2019 Dec 12. PMID:31857843 doi:http://dx.doi.org/10.1021/acsmedchemlett.9b00460
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