6qdb
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==Leishmania major N-myristoyltransferase in complex with thienopyrimidine inhibitor IMP-0000081== | ==Leishmania major N-myristoyltransferase in complex with thienopyrimidine inhibitor IMP-0000081== | ||
| - | <StructureSection load='6qdb' size='340' side='right'caption='[[6qdb]]' scene=''> | + | <StructureSection load='6qdb' size='340' side='right'caption='[[6qdb]], [[Resolution|resolution]] 1.40Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QDB OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[6qdb]] 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=6QDB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QDB FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.4Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HWQ:3-[methyl-[2-[methyl(piperidin-4-yl)amino]thieno[3,2-d]pyrimidin-4-yl]amino]propanenitrile'>HWQ</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=6qdb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qdb OCA], [https://pdbe.org/6qdb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6qdb RCSB], [https://www.ebi.ac.uk/pdbsum/6qdb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6qdb ProSAT]</span></td></tr> | ||
</table> | </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). | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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 (>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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6qdb" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| + | [[Category: Leishmania major]] | ||
[[Category: Brannigan JA]] | [[Category: Brannigan JA]] | ||
Current revision
Leishmania major N-myristoyltransferase in complex with thienopyrimidine inhibitor IMP-0000081
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