6E7F

Crystal Structure of Human Inositol Polyphosphate Multikinase (IPMK) Catalytic Core Domain

Replaces:  6C8A

Summary for 6E7F

• Entry DOI: 10.2210/pdb6e7f/pdb
• Descriptor: Inositol polyphosphate multikinase, SULFATE ION (3 entities in total)
• Functional Keywords: kinase, inositol phosphate, ipmk, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 64020.38

Authors

Blind, R.,Seacrist, C. (deposition date: 2018-07-26, release date: 2018-11-07, Last modification date: 2023-10-11)

Primary citation

Seacrist, C.D.,Blind, R.D.
Crystallographic and kinetic analyses of human IPMK reveal disordered domains modulate ATP binding and kinase activity.
Sci Rep, 8:16672-16672, 2018

PubMed Abstract: Inositol polyphosphate multikinase (IPMK) is a member of the IPK-superfamily of kinases, catalyzing phosphorylation of several soluble inositols and the signaling phospholipid PI(4,5)P (PIP). IPMK also has critical non-catalytic roles in p53, mTOR/Raptor, TRAF6 and AMPK signaling mediated partly by two disordered domains. Although IPMK non-catalytic functions are well established, it is less clear if the disordered domains are important for IPMK kinase activity or ATP binding. Here, kinetic and structural analyses of an engineered human IPMK lacking all disordered domains (ΔIPMK) are presented. Although the K for PIP is identical between ΔIPMK and wild type, ΔIPMK has a 1.8-fold increase in k for PIP, indicating the native IPMK disordered domains decrease IPMK activity in vitro. The 2.5 Å crystal structure of ΔIPMK is reported, confirming the conserved ATP-grasp fold. A comparison with other IPK-superfamily structures revealed a putative "ATP-clamp" in the disordered N-terminus, we predicted would stabilize ATP binding. Consistent with this observation, removal of the ATP clamp sequence increases the K for ATP 4.9-fold, indicating the N-terminus enhances ATP binding to IPMK. Together, these structural and kinetic studies suggest in addition to mediating protein-protein interactions, the disordered domains of IPMK impart modulatory capacity to IPMK kinase activity through multiple kinetic mechanisms.

PubMed: 30420721
DOI: 10.1038/s41598-018-34941-3

Experimental method

X-RAY DIFFRACTION (2.5 Å)