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6wj7

From Proteopedia

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Current revision

The structure of NTMT1 in complex with compound C2A

Structural highlights

6wj7 is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.42Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2] ^[3]

Publication Abstract from PubMed

The bisubstrate analogue strategy is a promising approach to develop potent and selective inhibitors for protein methyltransferases. Herein, the interactions of a series of bisubstrate analogues with protein N-terminal methyltransferase 1 (NTMT1) were examined to probe the molecular properties of the active site of NTMT1. Our results indicate that a 2-C to 4-C atom linker enables its respective bisubstrate analogue to occupy both substrate- and cofactor-binding sites of NTMT1, but the bisubstrate analogue with a 5-C atom linker only interacts with the substrate-binding site and functions as a substrate. Furthermore, the 4-C atom linker is the optimal and produces the most potent inhibitor (Ki,app = 130 +/- 40 pM) for NTMT1 to date, displaying more than 3000-fold selectivity for other methyltransferases and even for its homologue NTMT2. This study reveals the molecular basis for the plasticity of the active site of NTMT1. Additionally, our study outlines general guidance on the development of bisubstrate inhibitors for any methyltransferases.

Probing the Plasticity in the Active Site of Protein N-terminal Methyltransferase 1 Using Bisubstrate Analogues.,Chen D, Dong C, Dong G, Srinivasan K, Min J, Noinaj N, Huang R J Med Chem. 2020 Aug 13;63(15):8419-8431. doi: 10.1021/acs.jmedchem.0c00770. Epub, 2020 Jul 16. PMID:32605369^[4]

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

References

↑ Webb KJ, Lipson RS, Al-Hadid Q, Whitelegge JP, Clarke SG. Identification of protein N-terminal methyltransferases in yeast and humans. Biochemistry. 2010 Jun 29;49(25):5225-35. doi: 10.1021/bi100428x. PMID:20481588 doi:http://dx.doi.org/10.1021/bi100428x
↑ Tooley CE, Petkowski JJ, Muratore-Schroeder TL, Balsbaugh JL, Shabanowitz J, Sabat M, Minor W, Hunt DF, Macara IG. NRMT is an alpha-N-methyltransferase that methylates RCC1 and retinoblastoma protein. Nature. 2010 Aug 26;466(7310):1125-8. doi: 10.1038/nature09343. PMID:20668449 doi:http://dx.doi.org/10.1038/nature09343
↑ Petkowski JJ, Bonsignore LA, Tooley JG, Wilkey DW, Merchant ML, Macara IG, Schaner Tooley CE. NRMT2 is an N-terminal monomethylase that primes for its homologue NRMT1. Biochem J. 2013 Dec 15;456(3):453-62. doi: 10.1042/BJ20131163. PMID:24090352 doi:http://dx.doi.org/10.1042/BJ20131163
↑ Chen D, Dong C, Dong G, Srinivasan K, Min J, Noinaj N, Huang R. Probing the Plasticity in the Active Site of Protein N-terminal Methyltransferase 1 Using Bisubstrate Analogues. J Med Chem. 2020 Aug 13;63(15):8419-8431. PMID:32605369 doi:10.1021/acs.jmedchem.0c00770

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6wj7"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[6wj7]] is a 2 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=6WJ7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6WJ7 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AN6:5-{[(3S)-3-AMINO-3-CARBOXYPROPYL](ETHYL)AMINO}-5-DEOXYADENOSINE'>AN6</scene>, <scene name='pdbligand=GLZ:AMINO-ACETALDEHYDE'>GLZ</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</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]] 1.42&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AN6:5-{[(3S)-3-AMINO-3-CARBOXYPROPYL](ETHYL)AMINO}-5-DEOXYADENOSINE'>AN6</scene>, <scene name='pdbligand=GLZ:AMINO-ACETALDEHYDE'>GLZ</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</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=6wj7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wj7 OCA], [https://pdbe.org/6wj7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6wj7 RCSB], [https://www.ebi.ac.uk/pdbsum/6wj7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6wj7 ProSAT]</span></td></tr>
 </table>

6wj7

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Current revision

The structure of NTMT1 in complex with compound C2A

Structural highlights

Function

Publication Abstract from PubMed

References

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