7rwh: Difference between revisions

Latest revision as of 16:39, 18 October 2023

Crystal structure of human methionine adenosyltransferase 2A (MAT2A) in complex with SAM and allosteric inhibitor AGI-41998

Structural highlights

7rwh 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 1.17Å
Ligands:	1PE, 7UI, CL, EDO, GOL, MG, SAM
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

METK2_HUMAN Catalyzes the formation of S-adenosylmethionine from methionine and ATP.

Publication Abstract from PubMed

Inhibition of the S-adenosyl methionine (SAM)-producing metabolic enzyme, methionine adenosyltransferase 2A (MAT2A), has received significant interest in the field of medicinal chemistry due to its implication as a synthetic lethal target in cancers with the deletion of the methylthioadenosine phosphorylase (MTAP) gene. Here, we report the identification of novel MAT2A inhibitors with distinct in vivo properties that may enhance their utility in treating patients. Following a high-throughput screening, we successfully applied the structure-based design lessons from our first-in-class MAT2A inhibitor, AG-270, to rapidly redesign and optimize our initial hit into two new lead compounds: a brain-penetrant compound, AGI-41998, and a potent, but limited brain-penetrant compound, AGI-43192. We hope that the identification and first disclosure of brain-penetrant MAT2A inhibitors will create new opportunities to explore the potential therapeutic effects of SAM modulation in the central nervous system (CNS).

Leveraging Structure-Based Drug Design to Identify Next-Generation MAT2A Inhibitors, Including Brain-Penetrant and Peripherally Efficacious Leads.,Li M, Konteatis Z, Nagaraja N, Chen Y, Zhou S, Ma G, Gross S, Marjon K, Hyer ML, Mandley E, Lein M, Padyana AK, Jin L, Tong S, Peters R, Murtie J, Travins J, Medeiros M, Liu P, Frank V, Judd ET, Biller SA, Marks KM, Sui Z, Reznik SK J Med Chem. 2022 Mar 24;65(6):4600-4615. doi: 10.1021/acs.jmedchem.1c01595. Epub , 2022 Mar 16. PMID:35293760^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Li M, Konteatis Z, Nagaraja N, Chen Y, Zhou S, Ma G, Gross S, Marjon K, Hyer ML, Mandley E, Lein M, Padyana AK, Jin L, Tong S, Peters R, Murtie J, Travins J, Medeiros M, Liu P, Frank V, Judd ET, Biller SA, Marks KM, Sui Z, Reznik SK. Leveraging Structure-Based Drug Design to Identify Next-Generation MAT2A Inhibitors, Including Brain-Penetrant and Peripherally Efficacious Leads. J Med Chem. 2022 Mar 24;65(6):4600-4615. doi: 10.1021/acs.jmedchem.1c01595. Epub , 2022 Mar 16. PMID:35293760 doi:https://dx.doi.org/10.1021/acs.jmedchem.1c01595

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OCA

[1] Li M, Konteatis Z, Nagaraja N, Chen Y, Zhou S, Ma G, Gross S, Marjon K, Hyer ML, Mandley E, Lein M, Padyana AK, Jin L, Tong S, Peters R, Murtie J, Travins J, Medeiros M, Liu P, Frank V, Judd ET, Biller SA, Marks KM, Sui Z, Reznik SK. Leveraging Structure-Based Drug Design to Identify Next-Generation MAT2A Inhibitors, Including Brain-Penetrant and Peripherally Efficacious Leads. J Med Chem. 2022 Mar 24;65(6):4600-4615. doi: 10.1021/acs.jmedchem.1c01595. Epub , 2022 Mar 16. PMID:35293760 doi:https://dx.doi.org/10.1021/acs.jmedchem.1c01595

[1]

@@ Line 3: / Line 3: @@
 <StructureSection load='7rwh' size='340' side='right'caption='[[7rwh]], [[Resolution|resolution]] 1.17&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7rwh]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RWH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RWH FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7rwh]] 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=7RWH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RWH FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=7UI:8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-[2,2,2-tris(fluoranyl)ethylamino]pyrido[4,3-d]pyrimidin-7-ol'>7UI</scene>, <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=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</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]] 1.17&#8491;</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]], [[7rw5|7rw5]], [[7rw7|7rw7]], [[7rwg|7rwg]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=7UI:8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-[2,2,2-tris(fluoranyl)ethylamino]pyrido[4,3-d]pyrimidin-7-ol'>7UI</scene>, <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=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene></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=7rwh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rwh OCA], [https://pdbe.org/7rwh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rwh RCSB], [https://www.ebi.ac.uk/pdbsum/7rwh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rwh ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/METK2_HUMAN METK2_HUMAN]] Catalyzes the formation of S-adenosylmethionine from methionine and ATP.
+[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 ==
@@ Line 24: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Methionine adenosyltransferase]]
+[[Category: Jin L]]
-[[Category: Jin, L]]
+[[Category: Padyana AK]]
-[[Category: Padyana, A K]]
-[[Category: Allosteric inhibitor]]
-[[Category: Sam]]
-[[Category: Transferase]]
-[[Category: Transferase-inhibitor complex]]

7rwh: Difference between revisions

Latest revision as of 16:39, 18 October 2023

Crystal structure of human methionine adenosyltransferase 2A (MAT2A) in complex with SAM and allosteric inhibitor AGI-41998

Structural highlights

Function

Publication Abstract from PubMed

References

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