7u1m: Difference between revisions
New page: '''Unreleased structure''' The entry 7u1m is ON HOLD Authors: Description: Category: Unreleased Structures |
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The | ==Crystal structure of NTMT1 in complex with compound YD206== | ||
<StructureSection load='7u1m' size='340' side='right'caption='[[7u1m]], [[Resolution|resolution]] 3.17Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7u1m]] is a 2 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=7U1M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7U1M FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.17Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=KYF:(1R,3S,4R)-1-azabicyclo[2.2.2]octan-3-yl+{2-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]propan-2-yl}carbamate'>KYF</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</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=7u1m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7u1m OCA], [https://pdbe.org/7u1m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7u1m RCSB], [https://www.ebi.ac.uk/pdbsum/7u1m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7u1m ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/NTM1A_HUMAN NTM1A_HUMAN] Distributive alpha-N-methyltransferase that methylates the N-terminus of target proteins containing the N-terminal motif [Ala/Pro/Ser]-Pro-Lys when the initiator Met is cleaved. Specifically catalyzes mono-, di- or tri-methylation of exposed alpha-amino group of Ala or Ser residue in the [Ala/Ser]-Pro-Lys motif and mono- or di-methylation of Pro in the Pro-Pro-Lys motif. Some of the substrates may be primed by METTL11B-mediated monomethylation. Responsible for the N-terminal methylation of KLHL31, MYL2, MYL3, RB1, RCC1, RPL23A and SET. Required during mitosis for normal bipolar spindle formation and chromosome segregation via its action on RCC1.<ref>PMID:20481588</ref> <ref>PMID:20668449</ref> <ref>PMID:24090352</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Venglustat is a known allosteric inhibitor for ceramide glycosyltransferase, investigated in diseases caused by lysosomal dysfunction. Here, we identified venglustat as a potent inhibitor (IC(50) = 0.42 muM) of protein N-terminal methyltransferase 1 (NTMT1) by screening 58,130 compounds. Furthermore, venglustat exhibited selectivity for NTMT1 over 36 other methyltransferases. The crystal structure of NTMT1-venglustat and inhibition mechanism revealed that venglustat competitively binds at the peptide substrate site. Meanwhile, venglustat potently inhibited protein N-terminal methylation levels in cells (IC(50) = 0.5 muM). Preliminary structure-activity relationships indicated that the quinuclidine and fluorophenyl parts of venglustat are important for NTMT1 inhibition. In summary, we confirmed that venglustat is a bona fide NTMT1 inhibitor, which would advance the study on the biological roles of NTMT1. Additionally, this is the first disclosure of NTMT1 as a new molecular target of venglustat, which would cast light on its mechanism of action to guide the clinical investigations. | |||
Venglustat Inhibits Protein N-Terminal Methyltransferase 1 in a Substrate-Competitive Manner.,Dong G, Deng Y, Yasgar A, Yadav R, Talley D, Zakharov AV, Jain S, Rai G, Noinaj N, Simeonov A, Huang R J Med Chem. 2022 Sep 22;65(18):12334-12345. doi: 10.1021/acs.jmedchem.2c01050. , Epub 2022 Sep 8. PMID:36074125<ref>PMID:36074125</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7u1m" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Noinaj N]] | |||
[[Category: Yadav R]] | |||
Latest revision as of 12:49, 25 October 2023
Crystal structure of NTMT1 in complex with compound YD206Crystal structure of NTMT1 in complex with compound YD206
Structural highlights
FunctionNTM1A_HUMAN Distributive alpha-N-methyltransferase that methylates the N-terminus of target proteins containing the N-terminal motif [Ala/Pro/Ser]-Pro-Lys when the initiator Met is cleaved. Specifically catalyzes mono-, di- or tri-methylation of exposed alpha-amino group of Ala or Ser residue in the [Ala/Ser]-Pro-Lys motif and mono- or di-methylation of Pro in the Pro-Pro-Lys motif. Some of the substrates may be primed by METTL11B-mediated monomethylation. Responsible for the N-terminal methylation of KLHL31, MYL2, MYL3, RB1, RCC1, RPL23A and SET. Required during mitosis for normal bipolar spindle formation and chromosome segregation via its action on RCC1.[1] [2] [3] Publication Abstract from PubMedVenglustat is a known allosteric inhibitor for ceramide glycosyltransferase, investigated in diseases caused by lysosomal dysfunction. Here, we identified venglustat as a potent inhibitor (IC(50) = 0.42 muM) of protein N-terminal methyltransferase 1 (NTMT1) by screening 58,130 compounds. Furthermore, venglustat exhibited selectivity for NTMT1 over 36 other methyltransferases. The crystal structure of NTMT1-venglustat and inhibition mechanism revealed that venglustat competitively binds at the peptide substrate site. Meanwhile, venglustat potently inhibited protein N-terminal methylation levels in cells (IC(50) = 0.5 muM). Preliminary structure-activity relationships indicated that the quinuclidine and fluorophenyl parts of venglustat are important for NTMT1 inhibition. In summary, we confirmed that venglustat is a bona fide NTMT1 inhibitor, which would advance the study on the biological roles of NTMT1. Additionally, this is the first disclosure of NTMT1 as a new molecular target of venglustat, which would cast light on its mechanism of action to guide the clinical investigations. Venglustat Inhibits Protein N-Terminal Methyltransferase 1 in a Substrate-Competitive Manner.,Dong G, Deng Y, Yasgar A, Yadav R, Talley D, Zakharov AV, Jain S, Rai G, Noinaj N, Simeonov A, Huang R J Med Chem. 2022 Sep 22;65(18):12334-12345. doi: 10.1021/acs.jmedchem.2c01050. , Epub 2022 Sep 8. PMID:36074125[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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