7kdb: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Crystal structure of human methionine adenosyltransferase 2A (MAT2A) in complex with SAM and allosteric inhibitor compound 35== | ==Crystal structure of human methionine adenosyltransferase 2A (MAT2A) in complex with SAM and allosteric inhibitor compound 35== | ||
<StructureSection load='7kdb' size='340' side='right'caption='[[7kdb]]' scene=''> | <StructureSection load='7kdb' size='340' side='right'caption='[[7kdb]], [[Resolution|resolution]] 1.24Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KDB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KDB FirstGlance]. <br> | <table><tr><td colspan='2'>[[7kdb]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KDB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KDB FirstGlance]. <br> | ||
</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=7kdb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kdb OCA], [https://pdbe.org/7kdb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kdb RCSB], [https://www.ebi.ac.uk/pdbsum/7kdb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kdb ProSAT]</span></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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene>, <scene name='pdbligand=WBS:6-(4-hydroxyphenyl)-2,3-diphenyl-5-[(1H-pyrazol-3-yl)amino]pyrazolo[1,5-a]pyrimidin-7(4H)-one'>WBS</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7kcc|7kcc]], [[7kce|7kce]], [[7kcf|7kcf]], [[7kda|7kda]]</div></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=7kdb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kdb OCA], [https://pdbe.org/7kdb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kdb RCSB], [https://www.ebi.ac.uk/pdbsum/7kdb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kdb ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/METK2_HUMAN METK2_HUMAN]] Catalyzes the formation of S-adenosylmethionine from methionine and ATP. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was recently implicated as a synthetic lethal target in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene, which is adjacent to the CDKN2A tumor suppressor and codeleted with CDKN2A in approximately 15% of all cancers. Previous attempts to target MAT2A with small-molecule inhibitors identified cellular adaptations that blunted their efficacy. Here, we report the discovery of highly potent, selective, orally bioavailable MAT2A inhibitors that overcome these challenges. Fragment screening followed by iterative structure-guided design enabled >10000-fold improvement in potency of a family of allosteric MAT2A inhibitors that are substrate noncompetitive and inhibit release of the product, S-adenosyl methionine (SAM), from the enzyme's active site. We demonstrate that potent MAT2A inhibitors substantially reduce SAM levels in cancer cells and selectively block proliferation of MTAP-null cells both in tissue culture and xenograft tumors. These data supported progressing AG-270 into current clinical studies (ClinicalTrials.gov NCT03435250). | |||
Discovery of AG-270, a First-in-Class Oral MAT2A Inhibitor for the Treatment of Tumors with Homozygous MTAP Deletion.,Konteatis Z, Travins J, Gross S, Marjon K, Barnett A, Mandley E, Nicolay B, Nagaraja R, Chen Y, Sun Y, Liu Z, Yu J, Ye Z, Jiang F, Wei W, Fang C, Gao Y, Kalev P, Hyer ML, DeLaBarre B, Jin L, Padyana AK, Dang L, Murtie J, Biller SA, Sui Z, Marks KM J Med Chem. 2021 Apr 8. doi: 10.1021/acs.jmedchem.0c01895. PMID:33829783<ref>PMID:33829783</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7kdb" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Jin L]] | [[Category: Methionine adenosyltransferase]] | ||
[[Category: Padyana A]] | [[Category: Jin, L]] | ||
[[Category: Padyana, A]] | |||
[[Category: Allosteric inhibitor]] | |||
[[Category: Ethionine adenosyltransferase]] | |||
[[Category: Sam]] | |||
[[Category: Transferase]] | |||
[[Category: Transferase-inhibitor complex]] | |||
Revision as of 12:12, 5 May 2021
Crystal structure of human methionine adenosyltransferase 2A (MAT2A) in complex with SAM and allosteric inhibitor compound 35Crystal structure of human methionine adenosyltransferase 2A (MAT2A) in complex with SAM and allosteric inhibitor compound 35
Structural highlights
Function[METK2_HUMAN] Catalyzes the formation of S-adenosylmethionine from methionine and ATP. Publication Abstract from PubMedThe metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was recently implicated as a synthetic lethal target in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene, which is adjacent to the CDKN2A tumor suppressor and codeleted with CDKN2A in approximately 15% of all cancers. Previous attempts to target MAT2A with small-molecule inhibitors identified cellular adaptations that blunted their efficacy. Here, we report the discovery of highly potent, selective, orally bioavailable MAT2A inhibitors that overcome these challenges. Fragment screening followed by iterative structure-guided design enabled >10000-fold improvement in potency of a family of allosteric MAT2A inhibitors that are substrate noncompetitive and inhibit release of the product, S-adenosyl methionine (SAM), from the enzyme's active site. We demonstrate that potent MAT2A inhibitors substantially reduce SAM levels in cancer cells and selectively block proliferation of MTAP-null cells both in tissue culture and xenograft tumors. These data supported progressing AG-270 into current clinical studies (ClinicalTrials.gov NCT03435250). Discovery of AG-270, a First-in-Class Oral MAT2A Inhibitor for the Treatment of Tumors with Homozygous MTAP Deletion.,Konteatis Z, Travins J, Gross S, Marjon K, Barnett A, Mandley E, Nicolay B, Nagaraja R, Chen Y, Sun Y, Liu Z, Yu J, Ye Z, Jiang F, Wei W, Fang C, Gao Y, Kalev P, Hyer ML, DeLaBarre B, Jin L, Padyana AK, Dang L, Murtie J, Biller SA, Sui Z, Marks KM J Med Chem. 2021 Apr 8. doi: 10.1021/acs.jmedchem.0c01895. PMID:33829783[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||||