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| | <StructureSection load='5e2b' size='340' side='right'caption='[[5e2b]], [[Resolution|resolution]] 1.95Å' scene=''> | | <StructureSection load='5e2b' size='340' side='right'caption='[[5e2b]], [[Resolution|resolution]] 1.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5e2b]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5E2B OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5E2B FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5e2b]] is a 4 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=5E2B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5E2B FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</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]] 1.95Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=3BY:1-METHYL-L-PROLINE'>3BY</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3BY:1-METHYL-L-PROLINE'>3BY</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5e1d|5e1d]], [[5e2a|5e2a]], [[5e1m|5e1m]], [[5e1o|5e1o]], [[5e1b|5e1b]]</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=5e2b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5e2b OCA], [https://pdbe.org/5e2b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5e2b RCSB], [https://www.ebi.ac.uk/pdbsum/5e2b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5e2b ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein_N-terminal_methyltransferase Protein N-terminal methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.244 2.1.1.244] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5e2b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5e2b OCA], [http://pdbe.org/5e2b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5e2b RCSB], [http://www.ebi.ac.uk/pdbsum/5e2b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5e2b ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Protein N-terminal methyltransferase]]
| + | [[Category: Arrowsmith CH]] |
| - | [[Category: Arrowsmith, C H]] | + | [[Category: Bountra C]] |
| - | [[Category: Bountra, C]] | + | [[Category: Dong C]] |
| - | [[Category: Dong, C]] | + | [[Category: Edwards AM]] |
| - | [[Category: Edwards, A M]] | + | [[Category: Min J]] |
| - | [[Category: Min, J]] | + | [[Category: Tempel W]] |
| - | [[Category: Structural genomic]]
| + | |
| - | [[Category: Tempel, W]] | + | |
| - | [[Category: Sgc]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
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
alpha-N-terminal methylation represents a highly conserved and prevalent post-translational modification, yet its biological function has remained largely speculative. The recent discovery of alpha-N-terminal methyltransferase 1 (NTMT1) and its physiological substrates propels the elucidation of a general role of alpha-N-terminal methylation in mediating DNA-binding ability of the modified proteins. The phenotypes, observed from both NTMT1 knockdown in breast cancer cell lines and knockout mouse models, suggest the potential involvement of alpha-N-terminal methylation in DNA damage response and cancer development. In this study, we report the first crystal structures of human NTMT1 in complex with cofactor S-adenosyl-L-homocysteine (SAH) and six substrate peptides, respectively, and reveal that NTMT1 contains two characteristic structural elements (a beta hairpin and an N-terminal extension) that contribute to its substrate specificity. Our complex structures, coupled with mutagenesis, binding, and enzymatic studies, also present the key elements involved in locking the consensus substrate motif XPK (X indicates any residue type other than D/E) into the catalytic pocket for alpha-N-terminal methylation and explain why NTMT1 prefers an XPK sequence motif. We propose a catalytic mechanism for alpha-N-terminal methylation. Overall, this study gives us the first glimpse of the molecular mechanism of alpha-N-terminal methylation and potentially contributes to the advent of therapeutic agents for human diseases associated with deregulated alpha-N-terminal methylation.
Structural basis for substrate recognition by the human N-terminal methyltransferase 1.,Dong C, Mao Y, Tempel W, Qin S, Li L, Loppnau P, Huang R, Min J Genes Dev. 2015 Nov 15;29(22):2343-8. doi: 10.1101/gad.270611.115. Epub 2015 Nov , 5. PMID:26543161[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
- ↑ Dong C, Mao Y, Tempel W, Qin S, Li L, Loppnau P, Huang R, Min J. Structural basis for substrate recognition by the human N-terminal methyltransferase 1. Genes Dev. 2015 Nov 15;29(22):2343-8. doi: 10.1101/gad.270611.115. Epub 2015 Nov , 5. PMID:26543161 doi:http://dx.doi.org/10.1101/gad.270611.115
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