spacer
spacer

PDBsum entry 1pl0

Go to PDB code: 
protein ligands metals Protein-protein interface(s) links
Transferase, hydrolase PDB id
1pl0
Jmol
Contents
Protein chain
589 a.a. *
Ligands
XMP ×2
AMZ ×3
BW2 ×2
Metals
__K ×4
Waters ×388
* Residue conservation analysis
PDB id:
1pl0
Name: Transferase, hydrolase
Title: Crystal structure of human atic in complex with folate- based inhibitor, bw2315u89uc
Structure: Bifunctional purine biosynthesis protein purh. Chain: a, b, c, d. Synonym: atic. Engineered: yes. Other_details: includes: phosphoribosylaminoimidazolecarboxamide formyltransferase (aicar transformylase) and imp cyclohydrolase (inosinicase) (imp synthetase)
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: atic. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PQS)
Resolution:
2.60Å     R-factor:   0.213     R-free:   0.275
Authors: C.G.Cheong,S.E.Greasley,P.A.Horton,G.P.Beardsley,I.A.Wilson
Key ref:
C.G.Cheong et al. (2004). Crystal structures of human bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase in complex with potent sulfonyl-containing antifolates. J Biol Chem, 279, 18034-18045. PubMed id: 14966129 DOI: 10.1074/jbc.M313691200
Date:
06-Jun-03     Release date:   27-Apr-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P31939  (PUR9_HUMAN) -  Bifunctional purine biosynthesis protein PURH
Seq:
Struc:
 
Seq:
Struc:
592 a.a.
589 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: E.C.2.1.2.3  - Phosphoribosylaminoimidazolecarboxamide formyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
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
10-formyltetrahydrofolate
+ 5-amino-1-(5-phospho-D-ribosyl)imidazole-4- carboxamide
= tetrahydrofolate
+
5-formamido-1-(5-phospho-D- ribosyl)imidazole-4-carboxamide
Bound ligand (Het Group name = XMP)
corresponds exactly
   Enzyme class 3: E.C.3.5.4.10  - Imp cyclohydrolase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
      Reaction: IMP + H2O = 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide
IMP
+ H(2)O
=
5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide
Bound ligand (Het Group name = XMP)
corresponds exactly
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     membrane   4 terms 
  Biological process     brainstem development   17 terms 
  Biochemical function     catalytic activity     6 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M313691200 J Biol Chem 279:18034-18045 (2004)
PubMed id: 14966129  
 
 
Crystal structures of human bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase in complex with potent sulfonyl-containing antifolates.
C.G.Cheong, D.W.Wolan, S.E.Greasley, P.A.Horton, G.P.Beardsley, I.A.Wilson.
 
  ABSTRACT  
 
Aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/IMP cyclohydrolase (ATIC) is a bifunctional enzyme with folate-dependent AICAR transformylase and IMP cyclohydrolase activities that catalyzes the last two steps of purine biosynthesis. The AICAR transformylase inhibitors BW1540 and BW2315 are sulfamido-bridged 5,8-dideazafolate analogs with remarkably potent K(i) values of 8 and 6 nm, respectively, compared with most other antifolates. Crystal structures of ATIC at 2.55 and 2.60 A with each inhibitor, in the presence of substrate AICAR, revealed that the sulfonyl groups dominate inhibitor binding and orientation through interaction with the proposed oxyanion hole. These agents then appear to mimic the anionic transition state and now implicate Asn(431') in the reaction mechanism along with previously identified key catalytic residues Lys(266) and His(267). Potent and selective inhibition of the AICAR transformylase active site, compared with other folate-dependent enzymes, should therefore be pursued by further design of sulfonyl-containing antifolates.
 
  Selected figure(s)  
 
Figure 4.
FIG. 4. Comparison of the interactions of the AICAR Tfase active site with BW1540 and BW2315. A, schematic representation of the hydrogen bonding network and corresponding distances within the active site between AICAR, BW1540 and the AICAR Tfase residues. Interacting residues from the opposite subunit of the AICAR-bound monomer (black) are labeled in blue and indicated with a prime symbol. B, schematic representation of the hydrogen bonding network and corresponding distances within the AICAR Tfase active site with the bound AICAR and BW2315 molecules. Interacting residues from the opposite subunit of the AICAR-bound monomer (black) are labeled in blue and are indicated with a prime symbol.
Figure 5.
FIG. 5. Comparison of free and bound AICAR Tfase active sites. A, superposition of the AICAR- and antifolate-bound human AICAR Tfase active sites reveals slight translational and orientational deviations between the inhibitor molecules because of the propensity for the sulfonyl groups to be located in the oxyanion hole. The BW1540-bound structure is colored and labeled according to Fig. 3A. BW2315 carbons are colored orange with the BW2315-bound ATIC carbons and C trace colored in wheat. B, superposition of the BW1540-bound structure and the apo AICAR Tfase active sites reveals the slight conformational changes that occur upon folate binding. The BW1540-bound structure is colored and labeled according to Fig. 3A with the apo human ATIC C trace colored in wheat.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 18034-18045) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19207419 J.D.Durrant, R.E.Amaro, and J.A.McCammon (2009).
AutoGrow: a novel algorithm for protein inhibitor design.
  Chem Biol Drug Des, 73, 168-178.  
19212984 S.L.Cao, Y.W.Guo, X.B.Wang, M.Zhang, Y.P.Feng, Y.Y.Jiang, Y.Wang, Q.Gao, and J.Ren (2009).
Synthesis and cytotoxicity screening of piperazine-1-carbodithioate derivatives of 2-substituted quinazolin-4(3H)-ones.
  Arch Pharm (Weinheim), 342, 182-189.  
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.