6ht0

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of MLLT1 (ENL) YEATS domain in complexed with compound 94

Structural highlights

6ht0 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.8Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 (YD) containing proteins are an emerging class of epigenetic targets in drug discovery. Dysregulation of these modified lysine binding proteins has been linked to the onset and progression of cancers. We herein report the discovery and characterisation of the first small molecule chemical probe, SGC-iMLLT, for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). SGC-iMLLT is a potent and selective inhibitor of MLLT1/3 - histone interactions. Excellent selectivity over other human YD proteins (YEATS2/4) and bromodomains was observed. Furthermore, our probe displays cellular target engagement of MLLT1 and MLLT3. The first small molecule X-ray co-crystal structures with the MLLT1 YD are also reported. This first in class probe molecule can be used to understand MLLT1/3 associated biology and the therapeutic potential of small molecule YD inhibitors.

Discovery of an MLLT1/3 YEATS Domain Chemical Probe.,Moustakim M, Christott T, Monteiro OP, Bennett J, Giroud C, Ward J, Rogers CM, Smith P, Panagakou I, Saez LD, Felce SL, Gamble V, Gileadi C, Halidi N, Heidenreich D, Chaikuad A, Knapp S, Huber KVM, Farnie G, Heer J, Manevski N, Poda G, Al-Awar R, Dixon DJ, Fedorov O, Brennan P Angew Chem Int Ed Engl. 2018 Oct 5. doi: 10.1002/anie.201810617. PMID:30288907^[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
↑ Moustakim M, Christott T, Monteiro OP, Bennett J, Giroud C, Ward J, Rogers CM, Smith P, Panagakou I, Saez LD, Felce SL, Gamble V, Gileadi C, Halidi N, Heidenreich D, Chaikuad A, Knapp S, Huber KVM, Farnie G, Heer J, Manevski N, Poda G, Al-Awar R, Dixon DJ, Fedorov O, Brennan P. Discovery of an MLLT1/3 YEATS Domain Chemical Probe. Angew Chem Int Ed Engl. 2018 Oct 5. doi: 10.1002/anie.201810617. PMID:30288907 doi:http://dx.doi.org/10.1002/anie.201810617

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/6ht0"

@@ Line 1: / Line 1: @@
 ==Crystal structure of MLLT1 (ENL) YEATS domain in complexed with compound 94==
-<StructureSection load='6ht0' size='340' side='right' caption='[[6ht0]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
+<StructureSection load='6ht0' size='340' side='right'caption='[[6ht0]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6ht0]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HT0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HT0 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6ht0]] 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=6HT0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6HT0 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=GQ8:1-cyclopropyl-~{N}-[2-[[(2~{S})-2-methylpyrrolidin-1-yl]methyl]-3~{H}-benzimidazol-5-yl]indazole-5-carboxamide'>GQ8</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.8&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6ht1|6ht1]]</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=GQ8:1-cyclopropyl-~{N}-[2-[[(2~{S})-2-methylpyrrolidin-1-yl]methyl]-3~{H}-benzimidazol-5-yl]indazole-5-carboxamide'>GQ8</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6ht0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ht0 OCA], [http://pdbe.org/6ht0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ht0 RCSB], [http://www.ebi.ac.uk/pdbsum/6ht0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ht0 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=6ht0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ht0 OCA], [https://pdbe.org/6ht0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ht0 RCSB], [https://www.ebi.ac.uk/pdbsum/6ht0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ht0 ProSAT]</span></td></tr>
 </table>
 == 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 ==
-[[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;">
 == Publication Abstract from PubMed ==
@@ Line 25: / Line 25: @@
 __TOC__
 </StructureSection>
-[[Category: Arrowsmith, C H]]
+[[Category: Homo sapiens]]
-[[Category: Bountra, C]]
+[[Category: Large Structures]]
-[[Category: Brennan, P E]]
+[[Category: Arrowsmith CH]]
-[[Category: Chaikuad, A]]
+[[Category: Bountra C]]
-[[Category: Edwards, A M]]
+[[Category: Brennan PE]]
-[[Category: Fedorov, O]]
+[[Category: Chaikuad A]]
-[[Category: Heidenreich, D]]
+[[Category: Edwards AM]]
-[[Category: Knapp, S]]
+[[Category: Fedorov O]]
-[[Category: Moustakim, M]]
+[[Category: Heidenreich D]]
-[[Category: Structural genomic]]
+[[Category: Knapp S]]
-[[Category: Chemical probe]]
+[[Category: Moustakim M]]
-[[Category: Enl]]
-[[Category: Inhibitor]]
-[[Category: Mllt1]]
-[[Category: Sgc]]
-[[Category: Transcription]]
-[[Category: Yeats domain]]

6ht0

From Proteopedia

Current revision

Crystal structure of MLLT1 (ENL) YEATS domain in complexed with compound 94

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox