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PDBsum entry 6gnh
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PDB id:
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Transferase
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Title:
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Crystal structure of leishmania major n-myristoyltransferase (nmt) with bound myristoyl-coa and an azepanyl phenyl benzylsulphonamide ligand
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Structure:
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Glycylpeptide n-tetradecanoyltransferase. Chain: a. Engineered: yes
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Source:
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Leishmania major. Organism_taxid: 5664. Gene: nmt, lmjf_32_0080. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.89Å
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R-factor:
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0.172
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R-free:
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0.233
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Authors:
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D.A.Robinson,J.R.Harrison,S.Brand,V.C.Smith,S.Thompson,A.Smith, K.Davies,N.Y.Mok,L.S.Torrie,I.Collie,I.Hallyburton,S.Norval, F.R.C.Simeons,L.Stojanovski,J.A.Frearson,R.Brenk,P.G.Wyatt, I.H.Gilbert,K.D.Read
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Key ref:
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J.R.Harrison
et al.
(2018).
A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors.
J Med Chem,
61,
8374-8389.
PubMed id:
DOI:
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Date:
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30-May-18
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Release date:
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26-Sep-18
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PROCHECK
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Headers
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References
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Q4Q5S8
(Q4Q5S8_LEIMA) -
Glycylpeptide N-tetradecanoyltransferase from Leishmania major
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Seq:
Struc:
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421 a.a.
411 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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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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J Med Chem
61:8374-8389
(2018)
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PubMed id:
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A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors.
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J.R.Harrison,
S.Brand,
V.Smith,
D.A.Robinson,
S.Thompson,
A.Smith,
K.Davies,
N.Mok,
L.S.Torrie,
I.Collie,
I.Hallyburton,
S.Norval,
F.R.C.Simeons,
L.Stojanovski,
J.A.Frearson,
R.Brenk,
P.G.Wyatt,
I.H.Gilbert,
K.D.Read.
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ABSTRACT
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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.
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