2H31

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

2H31 の概要

• エントリーDOI: 10.2210/pdb2h31/pdb
• 分子名称: Multifunctional protein ADE2, CARBON DIOXIDE (3 entities in total)
• 機能のキーワード: alpha-beta-alpha, ligase, lyase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 47507.38

構造登録者

Li, S.-X.,Tong, Y.-P.,Xie, X.-C.,Li, S.-G.,Bi, R.-C. (登録日: 2006-05-21, 公開日: 2007-01-30, 最終更新日: 2024-10-23)

主引用文献

Li, S.X.,Tong, Y.P.,Xie, X.C.,Wang, Q.H.,Zhou, H.N.,Han, Y.,Zhang, Z.Y.,Gao, W.,Li, S.G.,Zhang, X.C.,Bi, R.C.
Octameric structure of the human bifunctional enzyme PAICS in purine biosynthesis.
J.Mol.Biol., 366:1603-1614, 2007

PubMed Abstract: 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.

PubMed: 17224163
DOI: 10.1016/j.jmb.2006.12.027

実験手法

X-RAY DIFFRACTION (2.8 Å)