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PDBsum entry 4cax
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PDB id:
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Transferase
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Title:
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Crystal structure of aspergillus fumigatus n-myristoyl transferase in complex with myristoyl coa and a pyrazole sulphonamide ligand (ddd85646)
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Structure:
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Glycylpeptide n-tetradecanoyltransferase. Chain: a. Fragment: residues 86-492. Synonym: myristoyl-coa\:protein n-myristoyltransferase, nmt, peptide n-myristoyltransferase. Engineered: yes
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Source:
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Aspergillus fumigatus. Organism_taxid: 746128. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: plyss.
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Resolution:
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1.85Å
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R-factor:
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0.225
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R-free:
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0.276
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Authors:
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O.G.Raimi,D.A.Robinson,W.Fang,D.E.Blair,J.Harrison,G.F.Ruda, D.E.A.Lockhart,L.S.Torrie,P.G.Wyatt,I.H.Gilbert,D.M.F.Van Aalten
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Key ref:
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W.Fang
et al.
(2015).
N-myristoyltransferase is a cell wall target in Aspergillus fumigatus.
Acs Chem Biol,
10,
1425-1434.
PubMed id:
DOI:
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Date:
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09-Oct-13
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Release date:
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17-Sep-14
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PROCHECK
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Headers
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References
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Q9UVX3
(NMT_ASPFU) -
Glycylpeptide N-tetradecanoyltransferase from Aspergillus fumigatus (strain ATCC MYA-4609 / CBS 101355 / FGSC A1100 / Af293)
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Seq:
Struc:
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492 a.a.
387 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.2.3.1.97
- glycylpeptide N-tetradecanoyltransferase.
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Reaction:
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N-terminal glycyl-[protein] + tetradecanoyl-CoA = N-tetradecanoylglycyl- [protein] + CoA + H+
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N-terminal glycyl-[protein]
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+
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tetradecanoyl-CoA
Bound ligand (Het Group name = )
corresponds exactly
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=
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N-tetradecanoylglycyl- [protein]
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+
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CoA
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Acs Chem Biol
10:1425-1434
(2015)
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PubMed id:
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N-myristoyltransferase is a cell wall target in Aspergillus fumigatus.
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W.Fang,
D.A.Robinson,
O.G.Raimi,
D.E.Blair,
J.R.Harrison,
D.E.Lockhart,
L.S.Torrie,
G.F.Ruda,
P.G.Wyatt,
I.H.Gilbert,
D.M.van Aalten.
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ABSTRACT
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Treatment of filamentous fungal infections relies on a limited repertoire of
antifungal agents. Compounds possessing novel modes of action are urgently
required. N-myristoylation is a ubiquitous modification of eukaryotic proteins.
The enzyme N-myristoyltransferase (NMT) has been considered a potential
therapeutic target in protozoa and yeasts. Here, we show that the filamentous
fungal pathogen Aspergillus fumigatus possesses an active NMT enzyme that is
essential for survival. Surprisingly, partial repression of the gene revealed
downstream effects of N-myristoylation on cell wall morphology. Screening a
library of inhibitors led to the discovery of a pyrazole sulphonamide compound
that inhibits the enzyme and is fungicidal under partially repressive nmt
conditions. Together with a crystallographic complex showing the inhibitor
binding in the peptide substrate pocket, we provide evidence of NMT being a
potential drug target in A. fumigatus.
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Links
