3mcn

Crystal Structure of the 6-hyroxymethyl-7,8-dihydropterin pyrophosphokinase dihydropteroate synthase bifunctional enzyme from Francisella tularensis

spinqualitylabelsall models 3mcn, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3mcn is a 2 chain structure with sequence from Francisella tularensis subsp. holarctica LVS. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.2Å Ligands: B57, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) and dihydropteroate synthase (DHPS) enzymes catalyze sequential metabolic reactions in the folate biosynthetic pathway of bacteria and lower eukaryotes. Both enzymes represent validated targets for the development of novel anti-microbial therapies. We report herein that the genes which encode FtHPPK and FtDHPS from the biowarfare agent Francisella tularensis are fused into a single polypeptide. The potential of simultaneously targeting both modules with pterin binding inhibitors prompted us to characterize the molecular details of the multifunctional complex. Our high resolution crystallographic analyses reveal the structural organization between FtHPPK and FtDHPS which are tethered together by a short linker. Additional structural analyses of substrate complexes reveal that the active sites of each module are virtually indistinguishable from those of the monofunctional enzymes. The fused bifunctional enzyme therefore represents an excellent vehicle for finding inhibitors that engage the pterin binding pockets of both modules that have entirely different architectures. To demonstrate that this approach has the potential of producing novel two-hit inhibitors of the folate pathway, we identify and structurally characterize a fragment-like molecule that simultaneously engages both active sites. Our study provides a molecular framework to study the enzyme mechanisms of HPPK and DHPS, and to design novel and much needed therapeutic compounds to treat infectious diseases. Crystal structure of the 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase*dihydropteroate synthase bifunctional enzyme from Francisella tularensis.,Pemble CW 4th, Mehta PK, Mehra S, Li Z, Nourse A, Lee RE, White SW PLoS One. 2010 Nov 30;5(11):e14165. PMID:21152407 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dihydropteroate synthase 3D structures HPPK 3D structures

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