|
|
| (One intermediate revision not shown.) |
| Line 3: |
Line 3: |
| | <StructureSection load='6chh' size='340' side='right'caption='[[6chh]], [[Resolution|resolution]] 2.30Å' scene=''> | | <StructureSection load='6chh' size='340' side='right'caption='[[6chh]], [[Resolution|resolution]] 2.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6chh]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CHH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CHH FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6chh]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=6b1a 6b1a]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CHH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CHH FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=F0P:(2~{S})-5-[2-(3-aminocarbonylphenyl)ethyl-[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl]amino]-2-azanyl-pentanoic+acid'>F0P</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]] 2.3Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NNMT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=F0P:(2~{S})-5-[2-(3-aminocarbonylphenyl)ethyl-[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl]amino]-2-azanyl-pentanoic+acid'>F0P</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Nicotinamide_N-methyltransferase Nicotinamide N-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.1 2.1.1.1] </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=6chh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6chh OCA], [https://pdbe.org/6chh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6chh RCSB], [https://www.ebi.ac.uk/pdbsum/6chh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6chh ProSAT]</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=6chh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6chh OCA], [http://pdbe.org/6chh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6chh RCSB], [http://www.ebi.ac.uk/pdbsum/6chh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6chh ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/NNMT_HUMAN NNMT_HUMAN]] Catalyzes the N-methylation of nicotinamide and other pyridines to form pyridinium ions. This activity is important for biotransformation of many drugs and xenobiotic compounds. | + | [https://www.uniprot.org/uniprot/NNMT_HUMAN NNMT_HUMAN] Catalyzes the N-methylation of nicotinamide and other pyridines to form pyridinium ions. This activity is important for biotransformation of many drugs and xenobiotic compounds. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 24: |
Line 23: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Nicotinamide N-methyltransferase]]
| + | [[Category: Babault N]] |
| - | [[Category: Babault, N]] | + | [[Category: Jin J]] |
| - | [[Category: Jin, J]] | + | [[Category: Liu J]] |
| - | [[Category: Liu, J]] | + | |
| - | [[Category: Protein-small molecule bisubstrate inhibitor complex]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Function
NNMT_HUMAN Catalyzes the N-methylation of nicotinamide and other pyridines to form pyridinium ions. This activity is important for biotransformation of many drugs and xenobiotic compounds.
Publication Abstract from PubMed
Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of pyridine-containing compounds using the cofactor S-5'-adenosyl-L-methionine (SAM) as the methyl group donor. Through the regulation of the levels of its substrates, cofactor, and products, NNMT plays important role in physiology and pathophysiology. Overexpression of NNMT has been implicated in various human diseases. Potent and selective small-molecule NNMT inhibitors are valuable chemical tools for testing biological and therapeutic hypotheses. However, very few NNMT inhibitors have been reported. Here, we describe the discovery of a bisubstrate NNMT inhibitor MS2734 (6), and characterization of this inhibitor in biochemical, biophysical, kinetic, and structural studies. Importantly, we obtained the first crystal structure of human NNMT in complex with a small-molecule inhibitor. The structure of the NNMT-6 complex has unambiguously demonstrated that 6 occupied both substrate and cofactor binding sites. The findings paved the way for developing more potent and selective NNMT inhibitors in the future.
Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT).,Babault N, Allali-Hassani A, Li F, Fan J, Yue A, Ju K, Liu F, Vedadi M, Liu J, Jin J J Med Chem. 2018 Jan 10. doi: 10.1021/acs.jmedchem.7b01422. PMID:29320176[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Babault N, Allali-Hassani A, Li F, Fan J, Yue A, Ju K, Liu F, Vedadi M, Liu J, Jin J. Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT). J Med Chem. 2018 Jan 10. doi: 10.1021/acs.jmedchem.7b01422. PMID:29320176 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01422
|
