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==Crystal Structure of Leishmania major N-Myristoyltransferase (NMT) With Bound Myristoyl-CoA and an Azepanyl Phenyl Benzylsulphonamide Ligand== | |||
<StructureSection load='6gnh' size='340' side='right' caption='[[6gnh]], [[Resolution|resolution]] 1.89Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6gnh]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GNH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GNH FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=F4T:methyl+4-(azepan-1-yl)-3-[(4-methoxyphenyl)sulfonylamino]benzoate'>F4T</scene>, <scene name='pdbligand=MYA:TETRADECANOYL-COA'>MYA</scene></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=6gnh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gnh OCA], [http://pdbe.org/6gnh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gnh RCSB], [http://www.ebi.ac.uk/pdbsum/6gnh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gnh 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 == | |||
Crystallography has guided the hybridization of two series of Trypanosoma brucei N-myristoyltransferase (NMT) inhibitors, leading to a novel highly selective series. The effect of combining the selectivity enhancing elements from two pharmacophores is shown to be additive and has led to compounds that have greater than 1000-fold selectivity for TbNMT vs HsNMT. Further optimization of the hybrid series has identified compounds with significant trypanocidal activity capable of crossing the blood-brain barrier. By using CF-1 mdr1a deficient mice, we were able to demonstrate full cures in vivo in a mouse model of stage 2 African sleeping sickness. This and previous work provides very strong validation for NMT as a drug target for human African trypanosomiasis in both the peripheral and central nervous system stages of disease. | |||
A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors.,Harrison JR, Brand S, Smith V, Robinson DA, Thompson S, Smith A, Davies K, Mok N, Torrie LS, Collie I, Hallyburton I, Norval S, Simeons FRC, Stojanovski L, Frearson JA, Brenk R, Wyatt PG, Gilbert IH, Read KD J Med Chem. 2018 Sep 12. doi: 10.1021/acs.jmedchem.8b00884. PMID:30207721<ref>PMID:30207721</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6gnh" 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: Collie, I]] | [[Category: Collie, I]] | ||
[[Category: Davies, K]] | [[Category: Davies, K]] | ||
[[Category: | [[Category: Frearson, J A]] | ||
[[Category: Gilbert, I | [[Category: Gilbert, I H]] | ||
[[Category: Hallyburton, I]] | [[Category: Hallyburton, I]] | ||
[[Category: Harrison, J R]] | |||
[[Category: Mok, N Y]] | |||
[[Category: Norval, S]] | |||
[[Category: Read, K D]] | |||
[[Category: Robinson, D A]] | |||
[[Category: Simeons, F R.C]] | |||
[[Category: Smith, A]] | |||
[[Category: Smith, V C]] | |||
[[Category: Stojanovski, L]] | [[Category: Stojanovski, L]] | ||
[[Category: Thompson, S]] | [[Category: Thompson, S]] | ||
[[Category: Torrie, L S]] | |||
[[Category: Wyatt, P G]] | |||
[[Category: Acyltransferase]] | |||
[[Category: Drug discovery]] | |||
[[Category: Transferase]] | |||
Revision as of 11:13, 26 September 2018
Crystal Structure of Leishmania major N-Myristoyltransferase (NMT) With Bound Myristoyl-CoA and an Azepanyl Phenyl Benzylsulphonamide LigandCrystal Structure of Leishmania major N-Myristoyltransferase (NMT) With Bound Myristoyl-CoA and an Azepanyl Phenyl Benzylsulphonamide 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 PubMedCrystallography has guided the hybridization of two series of Trypanosoma brucei N-myristoyltransferase (NMT) inhibitors, leading to a novel highly selective series. The effect of combining the selectivity enhancing elements from two pharmacophores is shown to be additive and has led to compounds that have greater than 1000-fold selectivity for TbNMT vs HsNMT. Further optimization of the hybrid series has identified compounds with significant trypanocidal activity capable of crossing the blood-brain barrier. By using CF-1 mdr1a deficient mice, we were able to demonstrate full cures in vivo in a mouse model of stage 2 African sleeping sickness. This and previous work provides very strong validation for NMT as a drug target for human African trypanosomiasis in both the peripheral and central nervous system stages of disease. A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors.,Harrison JR, Brand S, Smith V, Robinson DA, Thompson S, Smith A, Davies K, Mok N, Torrie LS, Collie I, Hallyburton I, Norval S, Simeons FRC, Stojanovski L, Frearson JA, Brenk R, Wyatt PG, Gilbert IH, Read KD J Med Chem. 2018 Sep 12. doi: 10.1021/acs.jmedchem.8b00884. PMID:30207721[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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