6ZJD

Crystal structure of human adenylate kinase 3, AK3, in complex with inhibitor ATP

6ZJD の概要

• エントリーDOI: 10.2210/pdb6zjd/pdb
• 分子名称: GTP:AMP phosphotransferase AK3, mitochondrial, ADENOSINE-5'-TRIPHOSPHATE, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: gtp:amp phosphotransferase, gp5a, transferase
• 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: 26307.52

構造登録者

Grundstrom, C.,Rogne, P.,Wolf-Watz, M.,Sauer-Eriksson, A.E. (登録日: 2020-06-28, 公開日: 2020-09-16, 最終更新日: 2024-01-31)

主引用文献

Rogne, P.,Dulko-Smith, B.,Goodman, J.,Rosselin, M.,Grundstrom, C.,Hedberg, C.,Nam, K.,Sauer-Eriksson, A.E.,Wolf-Watz, M.
Structural Basis for GTP versus ATP Selectivity in the NMP Kinase AK3.
Biochemistry, 59:3570-3581, 2020

PubMed Abstract: ATP and GTP are exceptionally important molecules in biology with multiple, and often discrete, functions. Therefore, enzymes that bind to either of them must develop robust mechanisms to selectively utilize one or the other. Here, this specific problem is addressed by molecular studies of the human NMP kinase AK3, which uses GTP to phosphorylate AMP. AK3 plays an important role in the citric acid cycle, where it is responsible for GTP/GDP recycling. By combining a structural biology approach with functional experiments, we present a comprehensive structural and mechanistic understanding of the enzyme. We discovered that AK3 functions by recruitment of GTP to the active site, while ATP is rejected and nonproductively bound to the AMP binding site. Consequently, ATP acts as an inhibitor with respect to GTP and AMP. The overall features with specific recognition of the correct substrate and nonproductive binding by the incorrect substrate bear a strong similarity to previous findings for the ATP specific NMP kinase adenylate kinase. Taken together, we are now able to provide the fundamental principles for GTP and ATP selectivity in the large NMP kinase family. As a side-result originating from nonlinearity of chemical shifts in GTP and ATP titrations, we find that protein surfaces offer a general and weak binding affinity for both GTP and ATP. These nonspecific interactions likely act to lower the available intracellular GTP and ATP concentrations and may have driven evolution of the Michaelis constants of NMP kinases accordingly.

PubMed: 32822537
DOI: 10.1021/acs.biochem.0c00549

実験手法

X-RAY DIFFRACTION (1.75 Å)