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7b10

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Current revision

Crystal structure of MLLT1 YEATS domain T1 mutant in complex with benzimidazole-amide based compound 1

Structural highlights

7b10 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 1.92Å
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

Dysfunction of YEATS-domain-containing MLLT1, an acetyl/acyl-lysine dependent epigenetic reader domain, has been implicated in the development of aggressive cancers. Mutations in the YEATS domain have been recently reported as a cause of MLLT1 aberrant reader function. However, the structural basis for the reported alterations in affinity for acetylated/acylated histone has remained elusive. Here, we report the crystal structures of both insertion and substitution mutants present in cancer, revealing significant conformational changes of the YEATS-domain loop 8. Structural comparison demonstrates that not only did such alteration alter the binding interface for acetylated/acylated histones, but the sequence alterations in the loop in T1 mutant may enable dimeric assembly consistent with inducing self-association behavior. Nevertheless, we show that also the MLLT1 mutants can be targeted by developed acetyllysine mimetic inhibitors with affinities similarly to wild-type. Our report provides a structural basis for the altered behaviors and a potential strategy for targeting oncogenic MLLT1 mutants.

Structure and Inhibitor Binding Characterization of Oncogenic MLLT1 Mutants.,Ni X, Londregan AT, Owen DR, Knapp S, Chaikuad A ACS Chem Biol. 2021 Mar 21. doi: 10.1021/acschembio.0c00960. PMID:33749253^[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, Londregan AT, Owen DR, Knapp S, Chaikuad A. Structure and Inhibitor Binding Characterization of Oncogenic MLLT1 Mutants. ACS Chem Biol. 2021 Mar 21. doi: 10.1021/acschembio.0c00960. PMID:33749253 doi:http://dx.doi.org/10.1021/acschembio.0c00960

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/7b10"

@@ Line 3: / Line 3: @@
 <StructureSection load='7b10' size='340' side='right'caption='[[7b10]], [[Resolution|resolution]] 1.92&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7b10]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7B10 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7B10 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7b10]] 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=7B10 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7B10 FirstGlance]. <br>
-</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=GKT:3-iodanyl-4-methyl-~{N}-[2-(piperidin-1-ylmethyl)-3~{H}-benzimidazol-5-yl]benzamide'>GKT</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</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]] 1.92&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MLLT1, ENL, LTG19, YEATS1 ([https://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=GKT:3-iodanyl-4-methyl-~{N}-[2-(piperidin-1-ylmethyl)-3~{H}-benzimidazol-5-yl]benzamide'>GKT</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></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=7b10 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7b10 OCA], [https://pdbe.org/7b10 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7b10 RCSB], [https://www.ebi.ac.uk/pdbsum/7b10 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7b10 ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[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.
+[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 ==
-[[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>
+[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: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Brennan, P E]]
+[[Category: Brennan PE]]
-[[Category: Chaikuad, A]]
+[[Category: Chaikuad A]]
-[[Category: Knapp, S]]
+[[Category: Knapp S]]
-[[Category: Ni, X]]
+[[Category: Ni X]]
-[[Category: Structural genomic]]
-[[Category: Sgc]]
-[[Category: T1 mutant]]
-[[Category: Transcription]]

7b10

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Current revision

Crystal structure of MLLT1 YEATS domain T1 mutant in complex with benzimidazole-amide based compound 1

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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