PDBsum entry 2iu3

Go to PDB code: 
protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
Protein chains
590 a.a. *
__K ×2
Waters ×97
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Crystal structures of transition state analogue inhibitors of inosine monophosphate cyclohydrolase
Structure: Bifunctional purine biosynthesis protein purh [includes\: phosphoribosylaminoimidazolecarboxamide formyltransferase]. Chain: a, b. Synonym: aminoimidazole carboxamide ribonucleotide transformylase and imp cyclohydrolase, atic, inosinicase, imp aicar transformylase cyclohydrolase, imp synthetase. Engineered: yes. Other_details: bifunctional enzyme
Source: Gallus gallus. Chicken. Organism_taxid: 9031. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_cell_line: bl21(de3).
2.90Å     R-factor:   0.215     R-free:   0.300
Authors: L.Xu,Y.Chong,I.Hwang,A.D'Onofrio,K.Amore,G.P.Beardsley,C.Li, A.J.Olson,D.L.Boger,I.A.Wilson
Key ref:
L.Xu et al. (2007). Structure-based design, synthesis, evaluation, and crystal structures of transition state analogue inhibitors of inosine monophosphate cyclohydrolase. J Biol Chem, 282, 13033-13046. PubMed id: 17324932 DOI: 10.1074/jbc.M607293200
27-May-06     Release date:   20-Feb-07    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P31335  (PUR9_CHICK) -  Bifunctional purine biosynthesis protein PURH
593 a.a.
590 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: E.C.  - Phosphoribosylaminoimidazolecarboxamide formyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Purine Biosynthesis (late stages)
      Reaction: 10-formyltetrahydrofolate + 5-amino-1-(5-phospho-D-ribosyl)imidazole-4- carboxamide = tetrahydrofolate + 5-formamido-1-(5-phospho-D- ribosyl)imidazole-4-carboxamide
+ 5-amino-1-(5-phospho-D-ribosyl)imidazole-4- carboxamide
= tetrahydrofolate
+ 5-formamido-1-(5-phospho-D- ribosyl)imidazole-4-carboxamide
   Enzyme class 3: E.C.  - Imp cyclohydrolase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Reaction: IMP + H2O = 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide
+ H(2)O
= 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytosol   1 term 
  Biological process     metabolic process   6 terms 
  Biochemical function     catalytic activity     6 terms  


DOI no: 10.1074/jbc.M607293200 J Biol Chem 282:13033-13046 (2007)
PubMed id: 17324932  
Structure-based design, synthesis, evaluation, and crystal structures of transition state analogue inhibitors of inosine monophosphate cyclohydrolase.
L.Xu, Y.Chong, I.Hwang, A.D'Onofrio, K.Amore, G.P.Beardsley, C.Li, A.J.Olson, D.L.Boger, I.A.Wilson.
The inosine monophosphate cyclohydrolase (IMPCH) component (residues 1-199) of the bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase (AICAR Tfase, residues 200-593)/IMPCH (ATIC) catalyzes the final step in the de novo purine biosynthesis pathway that produces IMP. As a potential target for antineoplastic intervention, we designed IMPCH inhibitors, 1,5-dihydroimidazo[4,5-c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide (heterocycle, 1), the corresponding nucleoside (2), and the nucleoside monophosphate (nucleotide) (3), as mimics of the tetrahedral intermediate in the cyclization reaction. All compounds are competitive inhibitors against IMPCH (K(i) values = 0.13-0.23 microm) with the simple heterocycle 1 exhibiting the most potent inhibition (K(i) = 0.13 microm). Crystal structures of bifunctional ATIC in complex with nucleoside 2 and nucleotide 3 revealed IMPCH binding modes similar to that of the IMPCH feedback inhibitor, xanthosine 5'-monophosphate. Surprisingly, the simpler heterocycle 1 had a completely different IMPCH binding mode and was relocated to the phosphate binding pocket that was identified from previous xanthosine 5'-monophosphate structures. The aromatic imidazole ring interacts with a helix dipole, similar to the interaction with the phosphate moiety of 3. The crystal structures not only revealed the mechanism of inhibition of these compounds, but they now serve as a platform for future inhibitor improvements. Importantly, the nucleoside-complexed structure supports the notion that inhibitors lacking a negatively charged phosphate can still inhibit IMPCH activity with comparable potency to phosphate-containing inhibitors. Provocatively, the nucleotide inhibitor 3 also binds to the AICAR Tfase domain of ATIC, which now provides a lead compound for the design of inhibitors that simultaneously target both active sites of this bifunctional enzyme.
  Selected figure(s)  
Figure 1.
FIGURE 1. Reactions of ATIC and the inhibitors of IMPCH. A, formyl transfer and cyclohydrolase reactions catalyzed by ATIC. B, proposed mechanism of IMP cyclization. The negatively charged tetrahedral intermediate is shown in brackets. The figure was adapted from Wolan et al. (8). C, the structures of IMPCH inhibitors in this study.
Figure 3.
FIGURE 3. Schematic drawing of IMPCH interactions with inhibitors. A, schematic illustration of IMPCH interactions with nucleotide 3, generated by LIGPLOT (28). Residues forming van der Waals' interactions are indicated by an arc with radiating spokes toward the ligand atom they contact; those residues participating in the hydrogen bonding are shown in ball-and-stick representations. Hydrogen bonds are illustrated as dotted lines and labeled in black (monomer D distances) or blue (monomer A distances). Water molecules are cyan, carbon atoms are black, and sulfurs are green; other atom types are colored as in Fig. 2A. B, schematic representation of IMPCH interactions with nucleoside 2. C, schematic drawing of IMPCH interactions of heterocycle 1.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 13033-13046) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
18712276 Y.Zhang, M.Morar, and S.E.Ealick (2008).
Structural biology of the purine biosynthetic pathway.
  Cell Mol Life Sci, 65, 3699-3724.  
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.