View source for 7ehz


==Structure of human NNMT in complex with macrocyclic peptide 2==
<StructureSection load='7ehz' size='340' side='right'caption='[[7ehz]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7ehz]] 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=7EHZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7EHZ 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]] 2.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DI8:(3S)-1,2,3,4-TETRAHYDROISOQUINOLINE-3-CARBOXYLIC+ACID'>DI8</scene>, <scene name='pdbligand=MEA:N-METHYLPHENYLALANINE'>MEA</scene>, <scene name='pdbligand=XA6:(2S)-3-(4-aminocarbonylphenyl)-2-azanyl-propanoic+acid'>XA6</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=7ehz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ehz OCA], [https://pdbe.org/7ehz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ehz RCSB], [https://www.ebi.ac.uk/pdbsum/7ehz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ehz ProSAT]</span></td></tr>
</table>
== Function ==
[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;">
== Publication Abstract from PubMed ==
Nicotinamide N-methyltransferase (NNMT), which catalyzes the methylation of nicotinamide, is a cytosolic enzyme that has attracted much attention as a therapeutic target for a variety of diseases. However, despite the considerable interest in this target, reports of NNMT inhibitors have still been limited to date. In this work, utilizing in vitro translated macrocyclic peptide libraries, we identified peptide 1 as a novel class of NNMT inhibitors. Further exploration based on the X-ray cocrystal structures of the peptides with NNMT provided a dramatic improvement in inhibitory activity (peptide 23: IC(50) = 0.15 nM). Furthermore, by balance of the peptides' lipophilicity and biological activity, inhibitory activity against NNMT in cell-based assay was successfully achieved (peptide 26: cell-based IC(50) = 770 nM). These findings illuminate the potential of cyclic peptides as a relatively new drug discovery modality even for intracellular targets.

Macrocyclic Peptides as a Novel Class of NNMT Inhibitors: A SAR Study Aimed at Inhibitory Activity in the Cell.,Hayashi K, Uehara S, Yamamoto S, Cary DR, Nishikawa J, Ueda T, Ozasa H, Mihara K, Yoshimura N, Kawai T, Ono T, Yamamoto S, Fumoto M, Mikamiyama H ACS Med Chem Lett. 2021 Jun 2;12(7):1093-1101. doi: , 10.1021/acsmedchemlett.1c00134. eCollection 2021 Jul 8. PMID:34267879<ref>PMID:34267879</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7ehz" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Cary D]]
[[Category: Fumoto M]]
[[Category: Hayashi K]]
[[Category: Kawai T]]
[[Category: Mihara K]]
[[Category: Mikamiyama H]]
[[Category: Nishikawa J]]
[[Category: Ono T]]
[[Category: Ozasa H]]
[[Category: Ueda T]]
[[Category: Uehara S]]
[[Category: Yamamoto S]]
[[Category: Yoshimura N]]