Center for Structural Genomics of Infectious Diseases

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Structure of IDP04072

CSGID target: IDP04072
PDB Id: 3OPQ (NCBI MMDB)
Authors: E.V.Filippova,Z.Wawrzak,M.Kudritska,A.Edwards,A.Savchenko,W.F.Anderson,Center For Structural Genomics Of Infectious Diseases (Csgid)
Responsible person: Ekaterina Filippova
Responsible lab: Northwestern University
Deposition Date: Sep 01, 2010
Release Date: Nov 17, 2010

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 2.00 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 phosphate and formate ions were found. Furthermore, two fructose-6-phosphates 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,catalyic subunit

Ligand code	Name	Ligand type
PO4		biological
CL	chloride	crystallization
FMT	formate	biological
MSE		modified residue
175	3,5-dihydro-5-methylidene-4h-imidazol-4-on

Space Group: P 21 21 21
Unit Cell: a=88.59Å, b=96.67Å, c=128.48Å
α=90.00, β=90.00, γ=90.00
Solvent content: 37.25
Matthews coefficient: 1.96
Resolution range: 77.25-2.00Å (2.05-2.00Å)
R_all(%): 19.1
R_work(%): 18.8 (22.1)
R_free(%): 23.6 (26.6)
Num. observed reflections: 74296 (5462)
Num. R_free reflections: 3714 (259)
Completeness(%): 98.8 (99.7)
Num Atoms: 9054
Num Waters: 480
Num Hetatoms: 1017
Model mean isotropic B factor: 21.800Å²
RMSD bond length: 0.016Å
RMSD bond angle: 1.477°
Filename uploaded: rcsb061418-update.pdb (uploaded on Sep 17, 2010 11:51 AM)
Inserted: Sep 17, 2010