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PDBsum entry 3mco

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protein ligands metals links
Transferase PDB id
3mco
Jmol
Contents
Protein chains
397 a.a. *
Ligands
PH2 ×4
APC ×2
Metals
_MG ×4
Waters ×57
* Residue conservation analysis
PDB id:
3mco
Name: Transferase
Title: Crystal structure of the 6-hyroxymethyl-7,8-dihydropterin pyrophosphokinase dihydropteroate synthase bifunctional enz francisella tularensis
Structure: 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase/dihydropteroate synthase. Chain: a, b. Engineered: yes
Source: Francisella tularensis subsp. Holarcti organism_taxid: 376619. Strain: lvs. Gene: folp/k, ftl_1265. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.30Å     R-factor:   0.243     R-free:   0.294
Authors: C.W.Pemble Iv,P.K.Mehta,S.Mehra,Z.Li,R.E.Lee,S.W.White
Key ref: C.W.Pemble et al. (2010). Crystal structure of the 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase•dihydropteroate synthase bifunctional enzyme from Francisella tularensis. PLoS One, 5, e14165. PubMed id: 21152407
Date:
29-Mar-10     Release date:   22-Dec-10    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q2A2W3  (Q2A2W3_FRATH) -  2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase/dihydropteroate synthase
Seq:
Struc:
421 a.a.
397 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     cellular metabolic process   4 terms 
  Biochemical function     dihydropteroate synthase activity     3 terms  

 

 
PLoS One 5:e14165 (2010)
PubMed id: 21152407  
 
 
Crystal structure of the 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase•dihydropteroate synthase bifunctional enzyme from Francisella tularensis.
C.W.Pemble, P.K.Mehta, S.Mehra, Z.Li, A.Nourse, R.E.Lee, S.W.White.
 
  ABSTRACT  
 
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.