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PDBsum entry 1rry

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Lyase PDB id
1rry
Jmol
Contents
Protein chain
121 a.a. *
Ligands
204
* Residue conservation analysis
PDB id:
1rry
Name: Lyase
Title: Dhna complexed with 2-amino-4-hydroxy-5-carboxyethylpyrimidi
Structure: Dihydroneopterin aldolase. Chain: a. Synonym: dhna. Engineered: yes
Source: Staphylococcus aureus. Organism_taxid: 1280. Gene: folb. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Octamer (from PDB file)
Resolution:
2.70Å     R-factor:   0.229     R-free:   0.305
Authors: W.J.Sanders,V.L.Nienaber,C.G.Lerner,J.O.Mccall,S.M.Merrick, S.J.Swanson,J.E.Harlan,V.S.Stoll,G.F.Stamper,S.F.Betz,K.R.C R.P.Meadows,J.M.Severin,K.A.Walter,P.Magdalinos,C.G.Jakob,R B.A.Beutel
Key ref: W.J.Sanders et al. (2004). Discovery of potent inhibitors of dihydroneopterin aldolase using CrystaLEAD high-throughput X-ray crystallographic screening and structure-directed lead optimization. J Med Chem, 47, 1709-1718. PubMed id: 15027862 DOI: 10.1021/jm030497y
Date:
09-Dec-03     Release date:   30-Mar-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P56740  (FOLB_STAAU) -  Dihydroneopterin aldolase
Seq:
Struc:
121 a.a.
121 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.4.1.2.25  - Dihydroneopterin aldolase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
Folate Biosynthesis (late stages)
      Reaction: 2-amino-4-hydroxy-6-(D-erythro-1,2,3-trihydroxypropyl)-7,8- dihydropteridine = 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine + glycolaldehyde
2-amino-4-hydroxy-6-(D-erythro-1,2,3-trihydroxypropyl)-7,8- dihydropteridine
=
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
Bound ligand (Het Group name = 204)
matches with 42.11% similarity
+ glycolaldehyde
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     folic acid-containing compound metabolic process   3 terms 
  Biochemical function     lyase activity     2 terms  

 

 
    Added reference    
 
 
DOI no: 10.1021/jm030497y J Med Chem 47:1709-1718 (2004)
PubMed id: 15027862  
 
 
Discovery of potent inhibitors of dihydroneopterin aldolase using CrystaLEAD high-throughput X-ray crystallographic screening and structure-directed lead optimization.
W.J.Sanders, V.L.Nienaber, C.G.Lerner, J.O.McCall, S.M.Merrick, S.J.Swanson, J.E.Harlan, V.S.Stoll, G.F.Stamper, S.F.Betz, K.R.Condroski, R.P.Meadows, J.M.Severin, K.A.Walter, P.Magdalinos, C.G.Jakob, R.Wagner, B.A.Beutel.
 
  ABSTRACT  
 
Potent inhibitors of 7,8-dihydroneopterin aldolase (DHNA; EC 4.1.2.25) have been discovered using CrystaLEAD X-ray crystallographic high-throughput screening followed by structure-directed optimization. Screening of a 10 000 compound random library provided several low affinity leads and their corresponding X-ray crystal structures bound to the enzyme. The presence of a common structural feature in each of the leads suggested a strategy for the construction of a directed library of approximately 1000 compounds that were screened for inhibitory activity in a traditional enzyme assay. Several lead compounds with IC(50) values of about 1 microM against DHNA were identified, and crystal structures of their enzyme-bound complexes were obtained by cocrystallization. Structure-directed optimization of one of the leads thus identified afforded potent inhibitors with submicromolar IC(50) values.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19443265 G.E.de Kloe, D.Bailey, R.Leurs, and I.J.de Esch (2009).
Transforming fragments into candidates: small becomes big in medicinal chemistry.
  Drug Discov Today, 14, 630-646.  
18621901 C.Tamae, A.Liu, K.Kim, D.Sitz, J.Hong, E.Becket, A.Bui, P.Solaimani, K.P.Tran, H.Yang, and J.H.Miller (2008).
Determination of antibiotic hypersensitivity among 4,000 single-gene-knockout mutants of Escherichia coli.
  J Bacteriol, 190, 5981-5988.  
  18931427 J.E.Spoonamore, S.A.Roberts, A.Heroux, and V.Bandarian (2008).
Structure of a 6-pyruvoyltetrahydropterin synthase homolog from Streptomyces coelicolor.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 64, 875-879.
PDB code: 3d7j
18316043 T.Hesterkamp, and M.Whittaker (2008).
Fragment-based activity space: smaller is better.
  Curr Opin Chem Biol, 12, 260-268.  
17581233 C.G.Lerner, P.J.Hajduk, R.Wagner, F.L.Wagenaar, C.Woodall, Y.G.Gu, X.B.Searle, A.S.Florjancic, T.Zhang, R.F.Clark, C.S.Cooper, J.C.Mack, L.Yu, M.Cai, S.F.Betz, L.E.Chovan, J.O.McCall, C.L.Black-Schaefer, S.J.Kakavas, M.E.Schurdak, K.M.Comess, K.A.Walter, R.Edalji, S.A.Dorwin, R.A.Smith, E.J.Hebert, J.E.Harlan, R.E.Metzger, P.J.Merta, J.L.Baranowski, M.L.Coen, S.J.Thornewell, A.G.Shivakumar, A.Y.Saiki, N.Soni, M.Bui, D.J.Balli, W.J.Sanders, A.M.Nilius, T.F.Holzman, S.W.Fesik, and B.A.Beutel (2007).
From bacterial genomes to novel antibacterial agents: discovery, characterization, and antibacterial activity of compounds that bind to HI0065 (YjeE) from Haemophilus influenzae.
  Chem Biol Drug Des, 69, 395-404.  
17331536 J.Blaszczyk, Y.Li, J.Gan, H.Yan, and X.Ji (2007).
Structural basis for the aldolase and epimerase activities of Staphylococcus aureus dihydroneopterin aldolase.
  J Mol Biol, 368, 161-169.
PDB codes: 2nm2 2nm3
17266529 J.E.Hyde (2007).
Targeting purine and pyrimidine metabolism in human apicomplexan parasites.
  Curr Drug Targets, 8, 31-47.  
17290284 P.J.Hajduk, and J.Greer (2007).
A decade of fragment-based drug design: strategic advances and lessons learned.
  Nat Rev Drug Discov, 6, 211-219.  
17388809 Y.Wang, Y.Li, Y.Wu, and H.Yan (2007).
Mechanism of dihydroneopterin aldolase. NMR, equilibrium and transient kinetic studies of the Staphylococcus aureus and Escherichia coli enzymes.
  FEBS J, 274, 2240-2252.  
16997145 A.Nzila (2006).
Inhibitors of de novo folate enzymes in Plasmodium falciparum.
  Drug Discov Today, 11, 939-944.  
17084612 D.A.Erlanson (2006).
Fragment-based lead discovery: a chemical update.
  Curr Opin Biotechnol, 17, 643-652.  
16846802 G.M.Keseru, and G.M.Makara (2006).
Hit discovery and hit-to-lead approaches.
  Drug Discov Today, 11, 741-748.  
17176045 Y.Wang, Y.Li, and H.Yan (2006).
Mechanism of dihydroneopterin aldolase: functional roles of the conserved active site glutamate and lysine residues.
  Biochemistry, 45, 15232-15239.  
15696598 A.Gill, A.Cleasby, and H.Jhoti (2005).
The discovery of novel protein kinase inhibitors by using fragment-based high-throughput x-ray crystallography.
  Chembiochem, 6, 506-512.  
15980348 C.G.Lerner, S.J.Kakavas, C.Wagner, R.T.Chang, P.J.Merta, X.Ruan, R.E.Metzger, and B.A.Beutel (2005).
Novel approach to mapping of resistance mutations in whole genomes by using restriction enzyme modulation of transformation efficiency.
  Antimicrob Agents Chemother, 49, 2767-2777.  
15925537 E.R.Zartler, and M.J.Shapiro (2005).
Fragonomics: fragment-based drug discovery.
  Curr Opin Chem Biol, 9, 366-370.  
15372084 M.B.Schmid (2004).
Seeing is believing: the impact of structural genomics on antimicrobial drug discovery.
  Nat Rev Microbiol, 2, 739-746.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.