7o2b

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Current revision (07:50, 1 May 2024) (edit) (undo)
 
Line 3: Line 3:
<StructureSection load='7o2b' size='340' side='right'caption='[[7o2b]], [[Resolution|resolution]] 2.03&Aring;' scene=''>
<StructureSection load='7o2b' size='340' side='right'caption='[[7o2b]], [[Resolution|resolution]] 2.03&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
-
<table><tr><td colspan='2'>[[7o2b]] 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=7O2B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7O2B FirstGlance]. <br>
+
<table><tr><td colspan='2'>[[7o2b]] 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=7O2B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7O2B FirstGlance]. <br>
-
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene>, <scene name='pdbligand=UZQ:(2S)-N-butyl-1-(2-fluorophenyl)carbonyl-2-methyl-4-oxidanylidene-3,5-dihydro-2H-1,5-benzodiazepine-7-carboxamide'>UZQ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.03&#8491;</td></tr>
-
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SMYD3, ZMYND1, ZNFN3A1 ([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=SAM:S-ADENOSYLMETHIONINE'>SAM</scene>, <scene name='pdbligand=UZQ:(2S)-N-butyl-1-(2-fluorophenyl)carbonyl-2-methyl-4-oxidanylidene-3,5-dihydro-2H-1,5-benzodiazepine-7-carboxamide'>UZQ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/[Histone_H3]-lysine(4)_N-trimethyltransferase [Histone H3]-lysine(4) N-trimethyltransferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.354 2.1.1.354] </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=7o2b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7o2b OCA], [https://pdbe.org/7o2b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7o2b RCSB], [https://www.ebi.ac.uk/pdbsum/7o2b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7o2b 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=7o2b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7o2b OCA], [https://pdbe.org/7o2b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7o2b RCSB], [https://www.ebi.ac.uk/pdbsum/7o2b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7o2b ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
-
[[https://www.uniprot.org/uniprot/SMYD3_HUMAN SMYD3_HUMAN]] Histone methyltransferase. Specifically methylates 'Lys-4' and 'Lys-5' of histone H3, inducing di- and tri-methylation, but not monomethylation. Plays an important role in transcriptional activation as a member of an RNA polymerase complex. Binds DNA containing 5'-CCCTCC-3' or 5'-GAGGGG-3' sequences.<ref>PMID:15235609</ref> <ref>PMID:22419068</ref>
+
[https://www.uniprot.org/uniprot/SMYD3_HUMAN SMYD3_HUMAN] Histone methyltransferase. Specifically methylates 'Lys-4' and 'Lys-5' of histone H3, inducing di- and tri-methylation, but not monomethylation. Plays an important role in transcriptional activation as a member of an RNA polymerase complex. Binds DNA containing 5'-CCCTCC-3' or 5'-GAGGGG-3' sequences.<ref>PMID:15235609</ref> <ref>PMID:22419068</ref>
-
<div style="background-color:#fffaf0;">
+
-
== Publication Abstract from PubMed ==
+
-
SMYD3 (SET and MYND domain-containing protein 3) is a protein lysine methyltransferase that was initially described as an H3K4 methyltransferase involved in transcriptional regulation. SMYD3 has been reported to methylate and regulate several nonhistone proteins relevant to cancer, including mitogen-activated protein kinase kinase kinase 2 (MAP3K2), vascular endothelial growth factor receptor 1 (VEGFR1), and the human epidermal growth factor receptor 2 (HER2). In addition, overexpression of SMYD3 has been linked to poor prognosis in certain cancers, suggesting SMYD3 as a potential oncogene and attractive cancer drug target. Here we report the discovery of a novel SMYD3 inhibitor. We performed a thermal shift assay (TSA)-based high-throughput screening (HTS) with 410,000 compounds and identified a novel benzodiazepine-based SMYD3 inhibitor series. Crystal structures revealed that this series binds to the substrate binding site and occupies the hydrophobic lysine binding pocket via an unprecedented hydrogen bonding pattern. Biochemical assays showed substrate competitive behavior. Following optimization and extensive biophysical validation with surface plasmon resonance (SPR) analysis and isothermal titration calorimetry (ITC), we identified BAY-6035, which shows nanomolar potency and selectivity against kinases and other PKMTs. Furthermore, BAY-6035 specifically inhibits methylation of MAP3K2 by SMYD3 in a cellular mechanistic assay with an IC50 &lt;100 nM. Moreover, we describe a congeneric negative control to BAY-6035. In summary, BAY-6035 is a novel selective and potent SMYD3 inhibitor probe that will foster the exploration of the biological role of SMYD3 in diseased and nondiseased tissues.
+
-
 
+
-
Discovery of the SMYD3 Inhibitor BAY-6035 Using Thermal Shift Assay (TSA)-Based High-Throughput Screening.,Gradl S, Steuber H, Weiske J, Szewczyk MM, Schmees N, Siegel S, Stoeckigt D, Christ CD, Li F, Organ S, Abbey M, Kennedy S, Chau I, Trush V, Barsyte-Lovejoy D, Brown PJ, Vedadi M, Arrowsmith C, Husemann M, Badock V, Bauser M, Haegebarth A, Hartung IV, Stresemann C SLAS Discov. 2021 Jun 21:24725552211019409. doi: 10.1177/24725552211019409. PMID:34154424<ref>PMID:34154424</ref>
+
-
 
+
-
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+
-
</div>
+
-
<div class="pdbe-citations 7o2b" style="background-color:#fffaf0;"></div>
+
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
-
[[Category: Human]]
+
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
-
[[Category: Steuber, H]]
+
[[Category: Steuber H]]
-
[[Category: Methyl transferase]]
+
-
[[Category: Smyd3]]
+
-
[[Category: Transferase]]
+

Current revision

X-RAY STRUCTURE OF SMYD3 in complex with benzodiazepine-type inhibitor 6

PDB ID 7o2b

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7o2b"
Personal tools