Center for Structural Genomics of Infectious Diseases

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Structure of IDP04072

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

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

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