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[[Image:4a31.png|left|200px]]
==CRYSTAL STRUCTURE OF LEISHMANIA MAJOR N-MYRISTOYLTRANSFERASE (NMT) WITH BOUND MYRISTOYL-COA AND A PYRAZOLE SULPHONAMIDE LIGAND==
<StructureSection load='4a31' size='340' side='right' caption='[[4a31]], [[Resolution|resolution]] 2.09&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4a31]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Leishmania_major Leishmania major]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4A31 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4A31 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2CB:6-{[2-(4-METHYLPIPERAZIN-1-YL)ETHYL]AMINO}-N-(1,3,5-TRIMETHYL-1H-PYRAZOL-4-YL)PYRIDINE-3-SULFONAMIDE'>2CB</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MYA:TETRADECANOYL-COA'>MYA</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4a32|4a32]], [[4a33|4a33]], [[4a30|4a30]], [[2wsa|2wsa]], [[4a2z|4a2z]]</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=4a31 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a31 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4a31 RCSB], [http://www.ebi.ac.uk/pdbsum/4a31 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 ==
N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report the optimization of a high throughput screening hit (1) to give a lead molecule DDD85646 (63), which has potent activity against the enzyme (IC(50) = 2 nM) and T. brucei (EC(50) = 2 nM) in culture. The compound has good oral pharmacokinetics and cures rodent models of peripheral HAT infection. This compound provides an excellent tool for validation of T. brucei NMT as a drug target for HAT as well as a valuable lead for further optimization.


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Discovery of a novel class of orally active trypanocidal N-myristoyltransferase inhibitors.,Brand S, Cleghorn LA, McElroy SP, Robinson DA, Smith VC, Hallyburton I, Harrison JR, Norcross NR, Spinks D, Bayliss T, Norval S, Stojanovski L, Torrie LS, Frearson JA, Brenk R, Fairlamb AH, Ferguson MA, Read KD, Wyatt PG, Gilbert IH J Med Chem. 2012 Jan 12;55(1):140-52. Epub 2011 Dec 7. PMID:22148754<ref>PMID:22148754</ref>
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{{STRUCTURE_4a31|  PDB=4a31  |  SCENE=  }}


===CRYSTAL STRUCTURE OF LEISHMANIA MAJOR N-MYRISTOYLTRANSFERASE (NMT) WITH BOUND MYRISTOYL-COA AND A PYRAZOLE SULPHONAMIDE LIGAND===
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 
</div>
 
== References ==
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{{ABSTRACT_PUBMED_22148754}}
 
==About this Structure==
[[4a31]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Leishmania_major Leishmania major]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4A31 OCA].
 
==Reference==
<ref group="xtra">PMID:022148754</ref><references group="xtra"/>
[[Category: Glycylpeptide N-tetradecanoyltransferase]]
[[Category: Glycylpeptide N-tetradecanoyltransferase]]
[[Category: Leishmania major]]
[[Category: Leishmania major]]
[[Category: Brand, S.]]
[[Category: Brand, S]]
[[Category: Brenk, R.]]
[[Category: Brenk, R]]
[[Category: Cleghorn, L A.T.]]
[[Category: Cleghorn, L A.T]]
[[Category: Fairlamb, A H.]]
[[Category: Fairlamb, A H]]
[[Category: Ferguson, M A.J.]]
[[Category: Ferguson, M A.J]]
[[Category: Frearson, J A.]]
[[Category: Frearson, J A]]
[[Category: Gilbert, I H.]]
[[Category: Gilbert, I H]]
[[Category: Hallyburton, I.]]
[[Category: Hallyburton, I]]
[[Category: Harrison, J R.]]
[[Category: Harrison, J R]]
[[Category: Mcelroy, S P.]]
[[Category: Mcelroy, S P]]
[[Category: Norcross, N R.]]
[[Category: Norcross, N R]]
[[Category: Norval, S.]]
[[Category: Norval, S]]
[[Category: Read, K D.]]
[[Category: Read, K D]]
[[Category: Robinson, D A.]]
[[Category: Robinson, D A]]
[[Category: Smith, V C.]]
[[Category: Smith, V C]]
[[Category: Spinks, D.]]
[[Category: Spinks, D]]
[[Category: Stojanovski, L.]]
[[Category: Stojanovski, L]]
[[Category: Torrie, L S.]]
[[Category: Torrie, L S]]
[[Category: Wyatt, P G.]]
[[Category: Wyatt, P G]]
[[Category: Acyltransferase]]
[[Category: Acyltransferase]]
[[Category: Drug discovery]]
[[Category: Drug discovery]]
[[Category: Leishmaniasis]]
[[Category: Leishmaniasis]]
[[Category: Transferase]]
[[Category: Transferase]]

Revision as of 20:31, 25 December 2014

CRYSTAL STRUCTURE OF LEISHMANIA MAJOR N-MYRISTOYLTRANSFERASE (NMT) WITH BOUND MYRISTOYL-COA AND A PYRAZOLE SULPHONAMIDE LIGANDCRYSTAL STRUCTURE OF LEISHMANIA MAJOR N-MYRISTOYLTRANSFERASE (NMT) WITH BOUND MYRISTOYL-COA AND A PYRAZOLE SULPHONAMIDE LIGAND

Structural highlights

4a31 is a 1 chain structure with sequence from Leishmania major. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, ,
Activity:Glycylpeptide N-tetradecanoyltransferase, with EC number 2.3.1.97
Resources:FirstGlance, OCA, RCSB, PDBsum

Function

[Q4Q5S8_LEIMA] Adds a myristoyl group to the N-terminal glycine residue of certain cellular proteins (By similarity).

Publication Abstract from PubMed

N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report the optimization of a high throughput screening hit (1) to give a lead molecule DDD85646 (63), which has potent activity against the enzyme (IC(50) = 2 nM) and T. brucei (EC(50) = 2 nM) in culture. The compound has good oral pharmacokinetics and cures rodent models of peripheral HAT infection. This compound provides an excellent tool for validation of T. brucei NMT as a drug target for HAT as well as a valuable lead for further optimization.

Discovery of a novel class of orally active trypanocidal N-myristoyltransferase inhibitors.,Brand S, Cleghorn LA, McElroy SP, Robinson DA, Smith VC, Hallyburton I, Harrison JR, Norcross NR, Spinks D, Bayliss T, Norval S, Stojanovski L, Torrie LS, Frearson JA, Brenk R, Fairlamb AH, Ferguson MA, Read KD, Wyatt PG, Gilbert IH J Med Chem. 2012 Jan 12;55(1):140-52. Epub 2011 Dec 7. PMID:22148754[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Brand S, Cleghorn LA, McElroy SP, Robinson DA, Smith VC, Hallyburton I, Harrison JR, Norcross NR, Spinks D, Bayliss T, Norval S, Stojanovski L, Torrie LS, Frearson JA, Brenk R, Fairlamb AH, Ferguson MA, Read KD, Wyatt PG, Gilbert IH. Discovery of a novel class of orally active trypanocidal N-myristoyltransferase inhibitors. J Med Chem. 2012 Jan 12;55(1):140-52. Epub 2011 Dec 7. PMID:22148754 doi:10.1021/jm201091t

4a31, resolution 2.09Å

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