View source for 7wmc


==Crystal structure of macrocyclic peptide 1 bound to human Nicotinamide N-methyltransferase==
<StructureSection load='7wmc' size='340' side='right'caption='[[7wmc]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7wmc]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Unidentified Unidentified]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WMC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WMC 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]] 2.55&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2IQ:2-(hexylamino)ethanoic+acid'>2IQ</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=7wmc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wmc OCA], [https://pdbe.org/7wmc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wmc RCSB], [https://www.ebi.ac.uk/pdbsum/7wmc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wmc 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 ==
Recent technological innovations have led to the development of methods for the rapid identification of high-affinity macrocyclic peptides for a wide range of targets; however, it is still challenging to achieve the desired activity and membrane permeability at the same time. Here, we propose a novel small molecule lead discovery strategy, ''Peptide-to-Small Molecule'', which is a combination of rapid identification of high-affinity macrocyclic peptides via peptide display screening followed by pharmacophore-guided de novo design of small molecules, and demonstrate the applicability using nicotinamide N-methyltransferase (NNMT) as a target. Affinity selection by peptide display technology identified macrocyclic peptide 1 that exhibited good enzymatic inhibitory activity but no cell-based activity. Thereafter, a peptide pharmacophore-guided de novo design and further structure-based optimization resulted in highly potent and cell-active small molecule 14 (cell-free IC50 = 0.0011 muM, cell-based IC50 = 0.40 muM), indicating that this strategy could be a new option for drug discovery.

Peptide-to-Small Molecule: A Pharmacophore-Guided Small Molecule Lead Generation Strategy from High-Affinity Macrocyclic Peptides.,Yoshida S, Uehara S, Kondo N, Takahashi Y, Yamamoto S, Kameda A, Kawagoe S, Inoue N, Yamada M, Yoshimura N, Tachibana Y J Med Chem. 2022 Aug 11;65(15):10655-10673. doi: 10.1021/acs.jmedchem.2c00919., Epub 2022 Jul 29. PMID:35904556<ref>PMID:35904556</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7wmc" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Unidentified]]
[[Category: Inoue N]]
[[Category: Kameda A]]
[[Category: Kawagoe S]]
[[Category: Kondo N]]
[[Category: Tachibana Y]]
[[Category: Takahashi Y]]
[[Category: Uehara S]]
[[Category: Yamada M]]
[[Category: Yamamoto S]]
[[Category: Yoshida S]]
[[Category: Yoshimura N]]