5db3

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5db3]] 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=5DB3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DB3 FirstGlance]. <br>
<table><tr><td colspan='2'>[[5db3]] 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=5DB3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DB3 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=58Q:6-METHOXY-4-METHYL-1-(1H-PYRAZOL-4-YLMETHYL)-5-[(4-{[6-(2,2,2-TRIFLUOROETHYL)THIENO[2,3-D]PYRIMIDIN-4-YL]AMINO}PIPERIDIN-1-YL)METHYL]-1H-INDOLE-2-CARBONITRILE'>58Q</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.71&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=58Q:6-METHOXY-4-METHYL-1-(1H-PYRAZOL-4-YLMETHYL)-5-[(4-{[6-(2,2,2-TRIFLUOROETHYL)THIENO[2,3-D]PYRIMIDIN-4-YL]AMINO}PIPERIDIN-1-YL)METHYL]-1H-INDOLE-2-CARBONITRILE'>58Q</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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'>[https://proteopedia.org/fgij/fg.htm?mol=5db3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5db3 OCA], [https://pdbe.org/5db3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5db3 RCSB], [https://www.ebi.ac.uk/pdbsum/5db3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5db3 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=5db3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5db3 OCA], [https://pdbe.org/5db3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5db3 RCSB], [https://www.ebi.ac.uk/pdbsum/5db3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5db3 ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
== Function ==
[https://www.uniprot.org/uniprot/MEN1_HUMAN MEN1_HUMAN] Essential component of a MLL/SET1 histone methyltransferase (HMT) complex, a complex that specifically methylates 'Lys-4' of histone H3 (H3K4). Functions as a transcriptional regulator. Binds to the TERT promoter and represses telomerase expression. Plays a role in TGFB1-mediated inhibition of cell-proliferation, possibly regulating SMAD3 transcriptional activity. Represses JUND-mediated transcriptional activation on AP1 sites, as well as that mediated by NFKB subunit RELA. Positively regulates HOXC8 and HOXC6 gene expression. May be involved in normal hematopoiesis through the activation of HOXA9 expression (By similarity). May be involved in DNA repair.<ref>PMID:11526476</ref> <ref>PMID:11274402</ref> <ref>PMID:12874027</ref> <ref>PMID:12837246</ref> <ref>PMID:14992727</ref>
[https://www.uniprot.org/uniprot/MEN1_HUMAN MEN1_HUMAN] Essential component of a MLL/SET1 histone methyltransferase (HMT) complex, a complex that specifically methylates 'Lys-4' of histone H3 (H3K4). Functions as a transcriptional regulator. Binds to the TERT promoter and represses telomerase expression. Plays a role in TGFB1-mediated inhibition of cell-proliferation, possibly regulating SMAD3 transcriptional activity. Represses JUND-mediated transcriptional activation on AP1 sites, as well as that mediated by NFKB subunit RELA. Positively regulates HOXC8 and HOXC6 gene expression. May be involved in normal hematopoiesis through the activation of HOXA9 expression (By similarity). May be involved in DNA repair.<ref>PMID:11526476</ref> <ref>PMID:11274402</ref> <ref>PMID:12874027</ref> <ref>PMID:12837246</ref> <ref>PMID:14992727</ref>
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<div style="background-color:#fffaf0;">
 
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== Publication Abstract from PubMed ==
 
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Development of potent small molecule inhibitors of protein-protein interactions with optimized druglike properties represents a challenging task in lead optimization process. Here, we report synthesis and structure-based optimization of new thienopyrimidine class of compounds, which block the protein-protein interaction between menin and MLL fusion proteins that plays an important role in acute leukemias with MLL translocations. We performed simultaneous optimization of both activity and druglike properties through systematic exploration of substituents introduced to the indole ring of lead compound 1 (MI-136) to identify compounds suitable for in vivo studies in mice. This work resulted in the identification of compound 27 (MI-538), which showed significantly increased activity, selectivity, polarity, and pharmacokinetic profile over 1 and demonstrated a pronounced effect in a mouse model of MLL leukemia. This study, which reports detailed structure-activity and structure-property relationships for the menin-MLL inhibitors, demonstrates challenges in optimizing inhibitors of protein-protein interactions for potential therapeutic applications.
 
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Property Focused Structure-Based Optimization of Small Molecule Inhibitors of the Protein-Protein Interaction between Menin and Mixed Lineage Leukemia (MLL).,Borkin D, Pollock J, Kempinska K, Purohit T, Li X, Wen B, Zhao T, Miao H, Shukla S, He M, Sun D, Cierpicki T, Grembecka J J Med Chem. 2016 Feb 11;59(3):892-913. doi: 10.1021/acs.jmedchem.5b01305. Epub, 2016 Jan 25. PMID:26744767<ref>PMID:26744767</ref>
 
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 
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</div>
 
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<div class="pdbe-citations 5db3" style="background-color:#fffaf0;"></div>
 
==See Also==
==See Also==

Current revision

Menin in complex with MI-574

PDB ID 5db3

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Proteopedia Page Contributors and Editors (what is this?)

OCA

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