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5e2b

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Revision as of 06:40, 22 April 2020

Crystal structure of NTMT1 in complex with N-terminally methylated PPKRIA peptide

Structural highlights

5e2b is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
NonStd Res:
Related:	5e1d, 5e2a, 5e1m, 5e1o, 5e1b
Activity:	Protein N-terminal methyltransferase, with EC number 2.1.1.244
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

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

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/5e2b"

@@ Line 1: / Line 1: @@
 ==Crystal structure of NTMT1 in complex with N-terminally methylated PPKRIA peptide==
-<StructureSection load='5e2b' size='340' side='right' caption='[[5e2b]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
+<StructureSection load='5e2b' size='340' side='right'caption='[[5e2b]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
 == 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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5E2B FirstGlance]. <br>
+<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>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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='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>
 <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='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='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://oca.weizmann.ac.il/oca-docs/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>
+<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>
 == Function ==
@@ Line 25: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Protein N-terminal methyltransferase]]
 [[Category: Arrowsmith, C H]]

5e2b

From Proteopedia

Revision as of 06:40, 22 April 2020

Crystal structure of NTMT1 in complex with N-terminally methylated PPKRIA peptide

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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