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Structure and activity of Yersinia pestis 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase as a novel target for the development of antiplague therapeutics
- Source :
- Acta crystallographica. Section D, Biological crystallography. 63(Pt 11)
- Publication Year :
- 2007
-
Abstract
- 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a key enzyme in the folate-biosynthetic pathway and is essential for microorganisms but absent from mammals. HPPK catalyzes Mg(2+)-dependent pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP). Previously, three-dimensional structures of Escherichia coli HPPK (EcHPPK) have been determined at almost every stage of its catalytic cycle and the reaction mechanism has been established. Here, the crystal structure of Yersinia pestis HPPK (YpHPPK) in complex with HP and an ATP analog is presented together with thermodynamic and kinetic characterizations. The two HPPK molecules differ significantly in a helix-loop area (alpha2-Lp3). YpHPPK has lower affinities than EcHPPK for both nucleotides and HP, but its rate constants for the mechanistic steps of both chemical transformation and product release are comparable with those of EcHPPK. Y. pestis, which causes plague, is a category A select agent according to the Centers for Disease Control and Prevention (CDC). Therefore, these structural and biochemical data are valuable for the design of novel medical countermeasures against plague.
- Subjects :
- Models, Molecular
Protein Conformation
Yersinia pestis
medicine.disease_cause
Crystallography, X-Ray
Catalysis
chemistry.chemical_compound
Adenosine Triphosphate
Structural Biology
medicine
Transferase
Animals
Humans
Nucleotide
Hydroxymethyl
Enzyme Inhibitors
Escherichia coli
chemistry.chemical_classification
Plague
Binding Sites
biology
General Medicine
biology.organism_classification
Disease control
Recombinant Proteins
Pterins
Kinetics
Enzyme
Catalytic cycle
chemistry
Biochemistry
Amino Acid Substitution
Drug Design
Diphosphotransferases
Thermodynamics
Dimerization
Subjects
Details
- ISSN :
- 09074449
- Volume :
- 63
- Issue :
- Pt 11
- Database :
- OpenAIRE
- Journal :
- Acta crystallographica. Section D, Biological crystallography
- Accession number :
- edsair.doi.dedup.....4a6de781b389bb001c4f53d6f918caf3