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''' | ==CRYSTAL STRUCTURE OF LEISHMANIA MAJOR N-MYRISTOYLTRANSFERASE (NMT) WITH BOUND MYRISTOYL-COA AND A BENZOMORPHOLINE LIGAND== | ||
<StructureSection load='5ag7' size='340' side='right' caption='[[5ag7]], [[Resolution|resolution]] 2.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5ag7]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AG7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AG7 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=XXL:ETHYL+(3-OXO-2,3-DIHYDRO-4H-1,4-BENZOXAZIN-4-YL)ACETATE'>XXL</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ag4|5ag4]], [[5ag5|5ag5]], [[5ag6|5ag6]], [[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=5ag7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ag7 OCA], [http://pdbe.org/5ag7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ag7 RCSB], [http://www.ebi.ac.uk/pdbsum/5ag7 PDBsum]</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 >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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5ag7" style="background-color:#fffaf0;"></div> | |||
[[Category: | == References == | ||
[[Category: | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Glycylpeptide N-tetradecanoyltransferase]] | |||
[[Category: Brand, S]] | |||
[[Category: Brenk, R]] | [[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, A]] | ||
[[Category: | [[Category: Smith, V C]] | ||
[[Category: Spinks, D]] | [[Category: Spinks, D]] | ||
[[Category: Thompson, S]] | [[Category: Thompson, S]] | ||
[[Category: Torrie, L S]] | |||
[[Category: Wyatt, P G]] | |||
[[Category: Acyltransferase]] | |||
[[Category: Drug discovery]] | |||
[[Category: N-myristoyltransferase]] | |||
[[Category: Nmt]] | |||
[[Category: Transferase]] | |||
Revision as of 16:45, 7 October 2015
CRYSTAL STRUCTURE OF LEISHMANIA MAJOR N-MYRISTOYLTRANSFERASE (NMT) WITH BOUND MYRISTOYL-COA AND A BENZOMORPHOLINE LIGANDCRYSTAL STRUCTURE OF LEISHMANIA MAJOR N-MYRISTOYLTRANSFERASE (NMT) WITH BOUND MYRISTOYL-COA AND A BENZOMORPHOLINE LIGAND
Structural highlights
Function[Q4Q5S8_LEIMA] Adds a myristoyl group to the N-terminal glycine residue of certain cellular proteins (By similarity). Publication Abstract from PubMedThe 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 >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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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