3X06

Crystal structure of PIP4KIIBETA T201M complex with GMP

Summary for 3X06

• Entry DOI: 10.2210/pdb3x06/pdb
• Related: 3WZZ 3X01 3X02 3X03 3X04 3X05 3X07 3X08 3X09 3X0A 3X0B 3X0C
• Descriptor: Phosphatidylinositol 5-phosphate 4-kinase type-2 beta, GUANOSINE-5'-MONOPHOSPHATE (3 entities in total)
• Functional Keywords: lipid kinase, phosphoinositide signaling, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane ; Peripheral membrane protein : P78356
• Total number of polymer chains: 2
• Total formula weight: 91734.10

Authors

Takeuchi, K.,Lo, Y.H.,Sumita, K.,Senda, M.,Terakawa, J.,Dimitoris, A.,Locasale, J.W.,Sasaki, M.,Yoshino, H.,Zhang, Y.,Kahoud, E.R.,Takano, T.,Yokota, T.,Emerling, B.,Asara, J.A.,Ishida, T.,Shimada, I.,Daikoku, T.,Cantley, L.C.,Senda, T.,Sasaki, A.T. (deposition date: 2014-10-09, release date: 2015-10-14, Last modification date: 2023-11-08)

Primary citation

Sumita, K.,Lo, Y.H.,Takeuchi, K.,Senda, M.,Kofuji, S.,Ikeda, Y.,Terakawa, J.,Sasaki, M.,Yoshino, H.,Majd, N.,Zheng, Y.,Kahoud, E.R.,Yokota, T.,Emerling, B.M.,Asara, J.M.,Ishida, T.,Locasale, J.W.,Daikoku, T.,Anastasiou, D.,Senda, T.,Sasaki, A.T.
The Lipid Kinase PI5P4K beta Is an Intracellular GTP Sensor for Metabolism and Tumorigenesis
Mol.Cell, 61:187-198, 2016

PubMed Abstract: While cellular GTP concentration dramatically changes in response to an organism's cellular status, whether it serves as a metabolic cue for biological signaling remains elusive due to the lack of molecular identification of GTP sensors. Here we report that PI5P4Kβ, a phosphoinositide kinase that regulates PI(5)P levels, detects GTP concentration and converts them into lipid second messenger signaling. Biochemical analyses show that PI5P4Kβ preferentially utilizes GTP, rather than ATP, for PI(5)P phosphorylation, and its activity reflects changes in direct proportion to the physiological GTP concentration. Structural and biological analyses reveal that the GTP-sensing activity of PI5P4Kβ is critical for metabolic adaptation and tumorigenesis. These results demonstrate that PI5P4Kβ is the missing GTP sensor and that GTP concentration functions as a metabolic cue via PI5P4Kβ. The critical role of the GTP-sensing activity of PI5P4Kβ in cancer signifies this lipid kinase as a cancer therapeutic target.

PubMed: 26774281
DOI: 10.1016/j.molcel.2015.12.011

Experimental method

X-RAY DIFFRACTION (2.65 Å)