2h31

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spinqualitylabelsall models 2h31, resolution 2.8Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of human PAICS, a bifunctional carboxylase and synthetase in purine biosynthesis

Overview

Phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole, succinocarboxamide synthetase (PAICS) is an important bifunctional enzyme, in de novo purine biosynthesis in vertebrate with both 5-aminoimidazole, ribonucleotide carboxylase (AIRc) and, 4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide synthetase, (SAICARs) activities. 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 human PAICS, the first in the entire PAICS family, at, 2.8 A resolution. It revealed that eight PAICS subunits, each composed of, distinct AIRc and SAICARs domains, assemble a compact homo-octamer with an, octameric-carboxylase core and four symmetric periphery dimers formed by, synthetase domains. Based on structural comparison and functional, complementation analyses, the active sites of SAICARs and AIRc were, identified, including a putative substrate CO(2)-binding site., Furthermore, four symmetry-related, separate tunnel systems in the PAICS, octamer were found that connect the active sites of AIRc and SAICARs. This, study illustrated the octameric nature of the bifunctional enzyme. Each, carboxylase active site is formed by structural elements from three AIRc, domains, demonstrating that the octamer structure is essential for the, carboxylation activity. Furthermore, the existence of the tunnel system, implies a mechanism of intermediate channeling and suggests that the, quaternary structure arrangement is crucial for effectively executing the, sequential reactions. In addition, this study provides essential, structural information for designing PAICS-specific inhibitors for use in, cancer chemotherapy.

About this Structure

2H31 is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.

Reference

Octameric structure of the human bifunctional enzyme PAICS in purine biosynthesis., Li SX, Tong YP, Xie XC, Wang QH, Zhou HN, Han Y, Zhang ZY, Gao W, Li SG, Zhang XC, Bi RC, J Mol Biol. 2007 Mar 9;366(5):1603-14. Epub 2006 Dec 16. PMID:17224163

Page seeded by OCA on Fri Feb 15 17:29:42 2008