6DQG

Human glutamate dehydrogenase, H454Y mutant

6DQG の概要

• エントリーDOI: 10.2210/pdb6dqg/pdb
• 分子名称: Glutamate dehydrogenase 1, mitochondrial, PHOSPHATE ION (3 entities in total)
• 機能のキーワード: glutamate, dehydrogenase, insulin, hyperinsulinism, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 332244.41

構造登録者

Smith, T.J. (登録日: 2018-06-10, 公開日: 2018-06-20, 最終更新日: 2024-03-13)

主引用文献

Nassar, O.M.,Li, C.,Stanley, C.A.,Pettitt, B.M.,Smith, T.J.
Glutamate dehydrogenase: Structure of a hyperinsulinism mutant, corrections to the atomic model, and insights into a regulatory site.
Proteins, 87:41-50, 2019

PubMed Abstract: Mammalian glutamate dehydrogenase (GDH) has complex allosteric regulation and the loss of GTP inhibition causes the hyperinsulinism/hyperammonemia syndrome (HHS) where insulin is hypersecreted upon consumption of protein. The archetypical HHS lesion is H454Y and lies in the GTP binding pocket. To better understand the mechanism of HHS, we determined the crystal structure of H454Y. When the bovine GDH crystal structures were minimized to prepare for further computational analysis, unusually large deviations were found at the allosteric NADH binding site due to chemical sequence errors. Notably, 387 lies in an allosteric where several activators and inhibitors bind and should be lysine rather than asparagine. All structures were re-refined and the consequence of this sequence error on NADH binding was calculated using free energy perturbation. The binding free energy penalty going from the correct to incorrect sequence found is +5 kcal/mol per site and therefore has a significant impact on drug development. BROADER AUDIENCE ABSTRACT: Glutamate dehydrogenase is a key enzyme involved in amino acid catabolism. As such, it is heavily regulated in animals by a wide array of metabolites. The importance of this regulation is most apparent in a genetic disorder called hyperinsulinism/hyperammonemia (HHS) where patients hypersecrete insulin upon the consumption of protein. We determined the atomic structure of one of these HHS mutants to better understand the disease and also analyzed an allosteric regulatory site.

PubMed: 30367518
DOI: 10.1002/prot.25620

実験手法

X-RAY DIFFRACTION (2.7 Å)