1WL4

Human cytosolic acetoacetyl-CoA thiolase complexed with CoA

1WL4 の概要

• エントリーDOI: 10.2210/pdb1wl4/pdb
• 関連するPDBエントリー: 1WL5
• 分子名称: acetyl-Coenzyme A acetyltransferase 2, SULFATE ION, COENZYME A, ... (5 entities in total)
• 機能のキーワード: thiolase fold, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: Q9BWD1
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 42742.74

構造登録者

Kursula, P.,Fukao, T.,Kondo, N.,Wierenga, R.K. (登録日: 2004-06-20, 公開日: 2005-03-01, 最終更新日: 2024-10-23)

主引用文献

Kursula, P.,Sikkila, H.,Fukao, T.,Kondo, N.,Wierenga, R.K.
High Resolution Crystal Structures of Human Cytosolic Thiolase (CT): A Comparison of the Active Sites of Human CT, Bacterial Thiolase, and Bacterial KAS I
J.Mol.Biol., 347:189-201, 2005

PubMed Abstract: Thiolases belong to a superfamily of condensing enzymes that includes also beta-ketoacyl acyl carrier protein synthases (KAS enzymes), involved in fatty acid synthesis. Here, we describe the high resolution structure of human cytosolic acetoacetyl-CoA thiolase (CT), both unliganded (at 2.3 angstroms resolution) and in complex with CoA (at 1.6 angstroms resolution). CT catalyses the condensation of two molecules of acetyl-CoA to acetoacetyl-CoA, which is the first reaction of the metabolic pathway leading to the synthesis of cholesterol. CT is a homotetramer of exact 222 symmetry. There is an excess of positively charged residues at the interdimer surface leading towards the CoA-binding pocket, possibly important for the efficient capture of substrates. The geometry of the catalytic site, including the three catalytic residues Cys92, His 353, Cys383, and the two oxyanion holes, is highly conserved between the human and bacterial Zoogloea ramigera thiolase. In human CT, the first oxyanion hole is formed by Wat38 (stabilised by Asn321) and NE2(His353), and the second by N(Cys92) and N(Gly385). The active site of this superfamily is constructed on top of four active site loops, near Cys92, Asn321, His353, and Cys383, respectively. These loops were used for the superpositioning of CT on the bacterial thiolase and on the Escherichia coli KAS I. This comparison indicates that the two thiolase oxyanion holes also exist in KAS I at topologically equivalent positions. Interestingly, the hydrogen bonding interactions at the first oxyanion hole are different in thiolase and KAS I. In KAS I, the hydrogen bonding partners are two histidine NE2 atoms, instead of a water and a NE2 side-chain atom in thiolase. The second oxyanion hole is in both structures shaped by corresponding main chain peptide NH-groups. The possible importance of bound water molecules at the catalytic site of thiolase for the reaction mechanism is discussed.

PubMed: 15733928
DOI: 10.1016/j.jmb.2005.01.018

実験手法

X-RAY DIFFRACTION (1.55 Å)