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PDBsum entry 4m5h
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Transferase/transferase inhibitor
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PDB id
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4m5h
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PDB id:
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| Name: |
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Transferase/transferase inhibitor
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Title:
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The identification, analysis and structure-based development of novel inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase
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Structure:
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2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase. Chain: a. Synonym: 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase, pppk, 7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase, hppk. Engineered: yes
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Source:
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Escherichia coli. Organism_taxid: 83333. Strain: k12. Gene: folk, b0142, jw0138. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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1.11Å
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R-factor:
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0.135
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R-free:
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0.149
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Authors:
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M.Yun,D.Hoagland,G.Kumar,B.Waddell,C.O.Rock,R.E.Lee,S.W.White
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Key ref:
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M.K.Yun
et al.
(2014).
The identification, analysis and structure-based development of novel inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase.
Bioorg Med Chem Lett,
22,
2157-2165.
PubMed id:
DOI:
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Date:
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08-Aug-13
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Release date:
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02-Apr-14
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PROCHECK
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Headers
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References
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P26281
(HPPK_ECOLI) -
2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase from Escherichia coli (strain K12)
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Seq:
Struc:
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159 a.a.
159 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.2.7.6.3
- 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase.
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Pathway:
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Folate Biosynthesis (late stages)
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Reaction:
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6-hydroxymethyl-7,8-dihydropterin + ATP = (7,8-dihydropterin-6-yl)methyl diphosphate + AMP + H+
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6-hydroxymethyl-7,8-dihydropterin
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+
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ATP
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=
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(7,8-dihydropterin-6-yl)methyl diphosphate
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+
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AMP
Bound ligand (Het Group name = )
matches with 68.75% similarity
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+
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H(+)
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Cofactor:
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Mg(2+)
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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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Bioorg Med Chem Lett
22:2157-2165
(2014)
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PubMed id:
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The identification, analysis and structure-based development of novel inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase.
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M.K.Yun,
D.Hoagland,
G.Kumar,
M.B.Waddell,
C.O.Rock,
R.E.Lee,
S.W.White.
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ABSTRACT
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6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is an essential
enzyme in the microbial folate biosynthetic pathway. This pathway has proven to
be an excellent target for antimicrobial development, but widespread resistance
to common therapeutics including the sulfa drugs has stimulated interest in HPPK
as an alternative target in the pathway. A screen of a pterin-biased compound
set identified several HPPK inhibitors that contain an aryl substituted
8-thioguanine scaffold, and structural analyses showed that these compounds
engage the HPPK pterin-binding pocket and an induced cryptic pocket. A
preliminary structure activity relationship profile was developed from
biophysical and biochemical characterizations of derivative molecules. Also, a
similarity search identified additional scaffolds that bind more tightly within
the HPPK pterin pocket. These inhibitory scaffolds have the potential for rapid
elaboration into novel lead antimicrobial agents.
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