View source for 6qdh


==Leishmania major N-myristoyltransferase in complex with quinazoline inhibitor IMP-0000906==
<StructureSection load='6qdh' size='340' side='right'caption='[[6qdh]], [[Resolution|resolution]] 1.45&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6qdh]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Leishmania_major Leishmania major]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QDH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QDH 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]] 1.45&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HXQ:4-[ethyl(methyl)amino]-2-[methyl-(1-methylpiperidin-4-yl)amino]-~{N}-(1,3,5-trimethylpyrazol-4-yl)quinazoline-6-sulfonamide'>HXQ</scene>, <scene name='pdbligand=HZ5:~{N}-(1,3,5-trimethylpyrazol-4-yl)methanesulfonamide'>HZ5</scene>, <scene name='pdbligand=HZ8:~{N}4-ethyl-~{N}2,~{N}4-dimethyl-~{N}2-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine'>HZ8</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MYA:TETRADECANOYL-COA'>MYA</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=6qdh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qdh OCA], [https://pdbe.org/6qdh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6qdh RCSB], [https://www.ebi.ac.uk/pdbsum/6qdh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6qdh ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q4Q5S8_LEIMA Q4Q5S8_LEIMA] Adds a myristoyl group to the N-terminal glycine residue of certain cellular proteins (By similarity).
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== Publication Abstract from PubMed ==
The leishmaniases, caused by Leishmania species of protozoan parasites, are neglected tropical diseases with millions of cases worldwide. Current therapeutic approaches are limited by toxicity, resistance, and cost. N-Myristoyltransferase (NMT), an enzyme ubiquitous and essential in all eukaryotes, has been validated via genetic and pharmacological methods as a promising anti-leishmanial target. Here we describe a comprehensive structure-activity relationship (SAR) study of a thienopyrimidine series previously identified in a high-throughput screen against Leishmania NMT, across 68 compounds in enzyme- and cell-based assay formats. Using a chemical tagging target engagement biomarker assay, we identify the first inhibitor in this series with on-target NMT activity in leishmania parasites. Furthermore, crystal structure analyses of 12 derivatives in complex with Leishmania major NMT revealed key factors important for future structure-guided optimization delivering IMP-105 (43), a compound with modest activity against Leishmania donovani intracellular amastigotes and excellent selectivity (&gt;660-fold) for Leishmania NMT over human NMTs.

Novel Thienopyrimidine Inhibitors of Leishmania N-Myristoyltransferase with On-Target Activity in Intracellular Amastigotes.,Bell AS, Yu Z, Hutton JA, Wright MH, Brannigan JA, Paape D, Roberts SM, Sutherell CL, Ritzefeld M, Wilkinson AJ, Smith DF, Leatherbarrow RJ, Tate EW J Med Chem. 2020 Jul 23;63(14):7740-7765. doi: 10.1021/acs.jmedchem.0c00570. Epub , 2020 Jul 14. PMID:32575985<ref>PMID:32575985</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6qdh" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Leishmania major]]
[[Category: Brannigan JA]]