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Structure of IDP04072

Octameric structure of the phosphoribosylaminoimidazole carboxylasecatalytic subunit from Francisella tularensis subsp. tularensis SCHU S4.

Edit deposit information
CSGID target
IDP04072 
PDB Id
3OOW (NCBI MMDB
Authors
E.V.Filippova,Z.Wawrzak,M.Kudritska,A.Edwards,A.Savchenko,F.W.Anderson,Center For Structural Genomics Of Infectious Diseases (Csgid) 
Responsible person
Ekaterina Filippova 
Responsible lab
Northwestern University 
Deposition Date
Aug 31, 2010 
Release Date
Sep 15, 2010 

Annotation

Description
Phosphoribosylaminoimidazole carboxylase/ phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) is a bifunctional enzyme with both 5-aminoimidazole ribonucleotide (AIR) carboxylase and 4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide (SAICAR) synthetase activities. PAICS is an important enzyme in de novo purine biosynthesis. It becomes an attractive target for rational anticancer drug design, since rapidly dividing cancer cells rely heavily on the purine de novo pathway for synthesis of adenine and guanine, whereas normal cells favor the salvage pathway. Here, we report the crystal structure of PAICS from Francisella tularensis subsp. tularensis SCHU S4 at 1.75 A resolution. The structure reveals that eight PAICS subunits, each composed of distinct AIRc and SAICARs domains, assemble a compact homooctamer with an octameric-carboxylase core and four symmetric periphery dimers formed by synthetase domains. At the carboxyaminoimidazole ribonucleotide active site two phosphate ions were found. Furthermore, four 2-methyl-2,4-pentanediol (MPD) were located at the central channel of the octameric protein structure. The structure provides structural information for designing PAICS-specific inhibitors for use in cancer chemotherapy.  
Functional assignment
Phosphoribosylaminoimidazole carboxylase catalytic subunit PurE 

Ligands

Ligand code Name Ligand type
PO4 PHOSPHATE ION crystallization
FMT crystallization
MPD crystallization
MSE modified residue
175 3,5-dihydro-5-methylidene-4h-imidazol-4-on

Structure information

Unit cell parameters

Space Group
P 21 21 21  
Unit Cell

a=88.56Å, b=96.30Å, c=128.62Å
α=90.00, β=90.00, γ=90.00 
Solvent content
36.08  
Matthews coefficient
1.92  

Refinement

Data for the highest resolution shell is in parentheses.
Resolution range
77.09-1.75Å (1.79-1.75Å)  
Rall(%)
17.0 
Rwork(%)
16.8 (21.8) 
Rfree(%)
20.5 (25.8) 
Num. observed reflections
109822 (8047) 
Num. Rfree reflections
5491 (404) 
Completeness(%)
98.7 (98.7) 

Model parameters

Num Atoms
9100  
Num Waters
545  
Num Hetatoms
1170  
Model mean isotropic B factor
20.700Å2  
RMSD bond length
0.017Å  
RMSD bond angle
1.500°  
Filename uploaded
3OOW.pdb (uploaded on Sep 17, 2010 4:50 PM)  
Inserted
Sep 08, 2010