View source for 6orr


==Co-crystal structure of human NicotinamideN-Methyltransferase (NNMT) in complex with High-Affinity Alkynyl Bisubstrate Inhibitor NS1==
<StructureSection load='6orr' size='340' side='right'caption='[[6orr]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6orr]] 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=6ORR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ORR 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]] 2.25&#8491;</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=N37:9-{9-amino-6-[(3-carbamoylphenyl)ethynyl]-5,6,7,8,9-pentadeoxy-D-glycero-alpha-L-talo-decofuranuronosyl}-9H-purin-6-amine'>N37</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=6orr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6orr OCA], [https://pdbe.org/6orr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6orr RCSB], [https://www.ebi.ac.uk/pdbsum/6orr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6orr 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) is a metabolic enzyme that methylates nicotinamide (NAM) using cofactor S-adenosylmethionine (SAM). NNMT overexpression has been linked to diabetes, obesity, and various cancers. In this work, structure-based rational design led to the development of potent and selective alkynyl bisubstrate inhibitors of NNMT. The reported nicotinamide-SAM conjugate (named NS1) features an alkyne as a key design element that closely mimics the linear, 180 degrees transition state geometry found in the NNMT-catalyzed SAM --&gt; NAM methyl transfer reaction. NS1 was synthesized in 14 steps and found to be a high-affinity, subnanomolar NNMT inhibitor. An X-ray co-crystal structure and SAR study revealed the ability of an alkynyl linker to span the methyl transfer tunnel of NNMT with ideal shape complementarity. The compounds reported in this work represent the most potent and selective NNMT inhibitors reported to date. The rational design principle described herein could potentially be extended to other methyltransferase enzymes.

High-Affinity Alkynyl Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT).,Policarpo RL, Decultot L, May E, Kuzmic P, Carlson S, Huang D, Chu V, Wright BA, Dhakshinamoorthy S, Kannt A, Rani S, Dittakavi S, Panarese JD, Gaudet R, Shair MD J Med Chem. 2019 Oct 7. doi: 10.1021/acs.jmedchem.9b01238. PMID:31589440<ref>PMID:31589440</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6orr" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Gaudet R]]
[[Category: May EJ]]
[[Category: Policarpo RL]]