7k3d: Difference between revisions
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==The structure of NTMT1 in complex with compound DC1-13== | ==The structure of NTMT1 in complex with compound DC1-13== | ||
<StructureSection load='7k3d' size='340' side='right'caption='[[7k3d]]' scene=''> | <StructureSection load='7k3d' size='340' side='right'caption='[[7k3d]], [[Resolution|resolution]] 2.34Å' 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=7K3D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7K3D FirstGlance]. <br> | <table><tr><td colspan='2'>[[7k3d]] 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=7K3D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7K3D 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=7k3d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k3d OCA], [https://pdbe.org/7k3d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7k3d RCSB], [https://www.ebi.ac.uk/pdbsum/7k3d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7k3d ProSAT]</span></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]] 2.34Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene>, <scene name='pdbligand=VWP:N~2~-{(2S)-1-[(naphthalen-1-yl)acetyl]-2,5-dihydro-1H-pyrrole-2-carbonyl}-L-lysyl-L-argininamide'>VWP</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=7k3d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k3d OCA], [https://pdbe.org/7k3d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7k3d RCSB], [https://www.ebi.ac.uk/pdbsum/7k3d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7k3d ProSAT]</span></td></tr> | |||
</table> | </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 == | |||
Protein N-terminal methyltransferases (NTMTs) catalyze the methylation of the alpha-N-terminal amines of proteins starting with an X-P-K/R motif. NTMT1 has been implicated in various cancers and in aging, implying its role as a potential therapeutic target. Through structural modifications of a lead NTMT1 inhibitor, BM30, we designed and synthesized a diverse set of inhibitors to probe the NTMT1 active site. The incorporation of a naphthyl group at the N-terminal region and an ortho-aminobenzoic amide at the C-terminal region of BM30 generates the top cell-potent inhibitor DC541, demonstrating increased activity on both purified NTMT1 (IC50 of 0.34 +/- 0.02 muM) and the cellular alpha-N-terminal methylation level of regulator of chromosome condensation 1 (RCC1, IC50 value of 30 muM) in human colorectal cancer HT29 cells. Furthermore, DC541 exhibits over 300-fold selectivity to several methyltransferases. This study points out the direction for the development of more cell-potent inhibitors for NTMT1. | |||
Structure-based Discovery of Cell-Potent Peptidomimetic Inhibitors for Protein N-Terminal Methyltransferase 1.,Chen D, Dong G, Deng Y, Noinaj N, Huang R ACS Med Chem Lett. 2021 Mar 1;12(3):485-493. doi: 10.1021/acsmedchemlett.1c00012., eCollection 2021 Mar 11. PMID:33738076<ref>PMID:33738076</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7k3d" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Chen D]] | [[Category: Chen D]] | ||
[[Category: Huang R]] | [[Category: Huang R]] | ||
[[Category: Noinaj N]] | [[Category: Noinaj N]] | ||
Latest revision as of 18:16, 18 October 2023
The structure of NTMT1 in complex with compound DC1-13The structure of NTMT1 in complex with compound DC1-13
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 PubMedProtein N-terminal methyltransferases (NTMTs) catalyze the methylation of the alpha-N-terminal amines of proteins starting with an X-P-K/R motif. NTMT1 has been implicated in various cancers and in aging, implying its role as a potential therapeutic target. Through structural modifications of a lead NTMT1 inhibitor, BM30, we designed and synthesized a diverse set of inhibitors to probe the NTMT1 active site. The incorporation of a naphthyl group at the N-terminal region and an ortho-aminobenzoic amide at the C-terminal region of BM30 generates the top cell-potent inhibitor DC541, demonstrating increased activity on both purified NTMT1 (IC50 of 0.34 +/- 0.02 muM) and the cellular alpha-N-terminal methylation level of regulator of chromosome condensation 1 (RCC1, IC50 value of 30 muM) in human colorectal cancer HT29 cells. Furthermore, DC541 exhibits over 300-fold selectivity to several methyltransferases. This study points out the direction for the development of more cell-potent inhibitors for NTMT1. Structure-based Discovery of Cell-Potent Peptidomimetic Inhibitors for Protein N-Terminal Methyltransferase 1.,Chen D, Dong G, Deng Y, Noinaj N, Huang R ACS Med Chem Lett. 2021 Mar 1;12(3):485-493. doi: 10.1021/acsmedchemlett.1c00012., eCollection 2021 Mar 11. PMID:33738076[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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