7bht: Difference between revisions
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<StructureSection load='7bht' size='340' side='right'caption='[[7bht]], [[Resolution|resolution]] 1.05Å' scene=''> | <StructureSection load='7bht' size='340' side='right'caption='[[7bht]], [[Resolution|resolution]] 1.05Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7bht]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7BHT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BHT FirstGlance]. <br> | <table><tr><td colspan='2'>[[7bht]] 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=7BHT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BHT FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene>, <scene name='pdbligand=TO8:7-chloranyl-4-(dimethylamino)-1~{H}-quinazolin-2-one'>TO8</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene>, <scene name='pdbligand=TO8:7-chloranyl-4-(dimethylamino)-1~{H}-quinazolin-2-one'>TO8</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAT2A, AMS2, MATA2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Methionine_adenosyltransferase Methionine adenosyltransferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.6 2.5.1.6] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Methionine_adenosyltransferase Methionine adenosyltransferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.6 2.5.1.6] </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=7bht FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bht OCA], [https://pdbe.org/7bht PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bht RCSB], [https://www.ebi.ac.uk/pdbsum/7bht PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bht 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=7bht FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bht OCA], [https://pdbe.org/7bht PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bht RCSB], [https://www.ebi.ac.uk/pdbsum/7bht PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bht ProSAT]</span></td></tr> | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Methionine adenosyltransferase]] | [[Category: Methionine adenosyltransferase]] | ||
Revision as of 15:30, 9 June 2021
Crystal structure of MAT2a with quinazolinone fragment 5 bound in the allosteric siteCrystal structure of MAT2a with quinazolinone fragment 5 bound in the allosteric site
Structural highlights
Function[METK2_HUMAN] Catalyzes the formation of S-adenosylmethionine from methionine and ATP. Publication Abstract from PubMedMAT2a is a methionine adenosyltransferase that synthesizes the essential metabolite S-adenosylmethionine (SAM) from methionine and ATP. Tumors bearing the co-deletion of p16 and MTAP genes have been shown to be sensitive to MAT2a inhibition, making it an attractive target for treatment of MTAP-deleted cancers. A fragment-based lead generation campaign identified weak but efficient hits binding in a known allosteric site. By use of structure-guided design and systematic SAR exploration, the hits were elaborated through a merging and growing strategy into an arylquinazolinone series of potent MAT2a inhibitors. The selected in vivo tool compound 28 reduced SAM-dependent methylation events in cells and inhibited proliferation of MTAP-null cells in vitro. In vivo studies showed that 28 was able to induce antitumor response in an MTAP knockout HCT116 xenograft model. Fragment-Based Design of a Potent MAT2a Inhibitor and in Vivo Evaluation in an MTAP Null Xenograft Model.,De Fusco C, Schimpl M, Borjesson U, Cheung T, Collie I, Evans L, Narasimhan P, Stubbs C, Vazquez-Chantada M, Wagner DJ, Grondine M, Sanders MG, Tentarelli S, Underwood E, Argyrou A, Smith JM, Lynch JT, Chiarparin E, Robb G, Bagal SK, Scott JS J Med Chem. 2021 Apr 26. doi: 10.1021/acs.jmedchem.1c00067. PMID:33900758[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Human
- Large Structures
- Methionine adenosyltransferase
- Argyrou, A
- Bagal, S
- Borjesson, U
- Cheung, T
- Chiarparin, E
- Collie, I
- Evans, L
- Fusco, C De
- Grondine, M
- Narasimhan, P
- Robb, G
- Schimpl, M
- Scott, J S
- Stubbs, C
- Tentarelli, S
- Underwood, E
- Vazquez-Chantada, M
- Wagner, D J
- Allosteric inhibitor
- Fragment-based drug design
- Oncology
- Synthetic lethal therapy
- Transferase