4YW8

Structure of rat cytosolic pepck in complex with 3-mercaptopicolinic acid

4YW8 の概要

• エントリーDOI: 10.2210/pdb4yw8/pdb
• 分子名称: Phosphoenolpyruvate carboxykinase, cytosolic [GTP], MANGANESE (II) ION, SODIUM ION, ... (8 entities in total)
• 機能のキーワード: kinase, gluconeogenesis, lyase, transferase
• 由来する生物種: Rattus norvegicus (Rat)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 70291.29

構造登録者

Balan, M.D.,Johnson, T.A.,Mcleod, M.J.,Lotosky, W.R.,Holyoak, T. (登録日: 2015-03-20, 公開日: 2015-09-23, 最終更新日: 2023-09-27)

主引用文献

Balan, M.D.,Mcleod, M.J.,Lotosky, W.R.,Ghaly, M.,Holyoak, T.
Inhibition and Allosteric Regulation of Monomeric Phosphoenolpyruvate Carboxykinase by 3-Mercaptopicolinic Acid.
Biochemistry, 54:5878-5887, 2015

PubMed Abstract: For almost 40 years, it has been known that tryptophan metabolites and picolinic acid analogues act as inhibitors of gluconeogenesis. Early studies observed that 3-mercaptopicolinic acid (MPA) was a potent hypoglycemic agent via inhibition of glucose synthesis through the specific inhibition of phosphoenolpyruvate carboxykinase (PEPCK) in the gluconeogenesis pathway. Despite prior kinetic investigation, the mechanism of the inhibition by MPA is unclear. To clarify the mechanism of inhibition exerted by MPA on PEPCK, we have undertaken structural and kinetic studies. The kinetic data in concert with crystallographic structures of PEPCK in complex with MPA and the substrates for the reaction illustrate that PEPCK is inhibited by the binding of MPA at two discrete binding sites: one acting in a competitive fashion with PEP/OAA (∼10 μM) and the other acting at a previously unidentified allosteric site (Ki ∼ 150 μM). The structural studies suggest that binding of MPA to the allosteric pocket stabilizes an altered conformation of the nucleotide-binding site that in turn reduces the affinity of the enzyme for the nucleotide.

PubMed: 26322521
DOI: 10.1021/acs.biochem.5b00822

実験手法

X-RAY DIFFRACTION (1.55 Å)