View source for 5ag4


==CRYSTAL STRUCTURE OF LEISHMANIA MAJOR N-MYRISTOYLTRANSFERASE (NMT) WITH BOUND MYRISTOYL-COA AND A THIAZOLIDINONE LIGAND==
<StructureSection load='5ag4' size='340' side='right'caption='[[5ag4]], [[Resolution|resolution]] 1.99&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ag4]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Leima Leima]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AG4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AG4 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MYA:TETRADECANOYL-COA'>MYA</scene>, <scene name='pdbligand=N8N:(2S)-3-(3-CHLOROPHENYL)-2-(PYRIDIN-2-YL)-1,3-THIAZOLIDIN-4-ONE'>N8N</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ag5|5ag5]], [[5ag6|5ag6]], [[5ag7|5ag7]], [[5age|5age]]</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glycylpeptide_N-tetradecanoyltransferase Glycylpeptide N-tetradecanoyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.97 2.3.1.97] </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=5ag4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ag4 OCA], [http://pdbe.org/5ag4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ag4 RCSB], [http://www.ebi.ac.uk/pdbsum/5ag4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ag4 ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/Q4Q5S8_LEIMA Q4Q5S8_LEIMA]] Adds a myristoyl group to the N-terminal glycine residue of certain cellular proteins (By similarity). 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The enzyme N-myristoyltransferase (NMT) from Trypanosoma brucei has been validated both chemically and biologically as a potential drug target for human African trypanosomiasis. We previously reported the development of some very potent compounds based around a pyrazole sulfonamide series, derived from a high-throughput screen. Herein we describe work around thiazolidinone and benzomorpholine scaffolds that were also identified in the screen. An X-ray crystal structure of the thiazolidinone hit in Leishmania major NMT showed the compound bound in the previously reported active site, utilising a novel binding mode. This provides potential for further optimisation. The benzomorpholinone was also found to bind in a similar region. Using an X-ray crystallography/structure-based design approach, the benzomorpholinone series was further optimised, increasing activity against T. brucei NMT by &gt;1000-fold. A series of trypanocidal compounds were identified with suitable in vitro DMPK properties, including CNS exposure for further development. Further work is required to increase selectivity over the human NMT isoform and activity against T. brucei.

Development of Small-Molecule Trypanosoma brucei N-Myristoyltransferase Inhibitors: Discovery and Optimisation of a Novel Binding Mode.,Spinks D, Smith V, Thompson S, Robinson DA, Luksch T, Smith A, Torrie LS, McElroy S, Stojanovski L, Norval S, Collie IT, Hallyburton I, Rao B, Brand S, Brenk R, Frearson JA, Read KD, Wyatt PG, Gilbert IH ChemMedChem. 2015 Sep 23. doi: 10.1002/cmdc.201500301. PMID:26395087<ref>PMID:26395087</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5ag4" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Glycylpeptide N-tetradecanoyltransferase]]
[[Category: Large Structures]]
[[Category: Leima]]
[[Category: Brand, S]]
[[Category: Brenk, R]]
[[Category: Frearson, J A]]
[[Category: Gilbert, I H]]
[[Category: McElroy, S P]]
[[Category: Read, K D]]
[[Category: Robinson, D A]]
[[Category: Smith, A]]
[[Category: Smith, V C]]
[[Category: Spinks, D]]
[[Category: Thompson, S]]
[[Category: Torrie, L S]]
[[Category: Wyatt, P G]]
[[Category: Acyltransferase]]
[[Category: Drug discovery]]
[[Category: Nmt]]
[[Category: Transferase]]