6wh8: Difference between revisions
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<table><tr><td colspan='2'>[[6wh8]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6WH8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6WH8 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6wh8]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6WH8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6WH8 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]] 1.729Å</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]] 1.729Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4HP:4-HYDROXYPHENYLACETATE'>4HP</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2 | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4HP:4-HYDROXYPHENYLACETATE'>4HP</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</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=6wh8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wh8 OCA], [https://pdbe.org/6wh8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6wh8 RCSB], [https://www.ebi.ac.uk/pdbsum/6wh8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6wh8 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=6wh8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wh8 OCA], [https://pdbe.org/6wh8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6wh8 RCSB], [https://www.ebi.ac.uk/pdbsum/6wh8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6wh8 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
Latest revision as of 13:38, 23 October 2024
The structure of NTMT1 in complex with compound BM-30The structure of NTMT1 in complex with compound BM-30
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) methylate the alpha-N-terminal amines of proteins starting with the canonical X-P-K/R motif. Genetic studies imply that NTMT1 regulates cell mitosis and DNA damage repair. Herein, we report the rational design and development of the first potent peptidomimetic inhibitor for NTMT1/2. Biochemical and cocrystallization studies manifest that BM30 (with a half-maximal inhibitory concentration of 0.89 +/- 0.10 muM) is a competitive inhibitor to the peptide substrate and noncompetitive to the cofactor S-adenosylmethionine. BM30 exhibits over 100-fold selectivity to NTMT1/2 among a panel of 41 MTs, indicating its potential to achieve high selectivity when targeting the peptide substrate binding site of NTMT1/2. Its cell-permeable analogue DC432 (IC(50) of 54 +/- 4 nM) decreases the N-terminal methylation level of the regulator of chromosome condensation 1 and SET proteins in HCT116 cells. This proof-of principle study provides valuable probes for NTMT1/2 and highlights the opportunity to develop more cell-potent inhibitors to elucidate the function of NTMTs in the future. Selective Peptidomimetic Inhibitors of NTMT1/2: Rational Design, Synthesis, Characterization, and Crystallographic Studies.,Mackie BD, Chen D, Dong G, Dong C, Parker H, Schaner Tooley CE, Noinaj N, Min J, Huang R J Med Chem. 2020 Sep 10;63(17):9512-9522. doi: 10.1021/acs.jmedchem.0c00689. Epub , 2020 Aug 5. PMID:32689795[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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