6cmw | pdb_00006cmw

Crystal structure of zebrafish Phosphatidylinositol-4-phosphate 5- kinase alpha isoform with bound ATP/Ca2+

spinqualitylabelsall models 6cmw, resolution 3.15Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6cmw is a 1 chain structure with sequence from Brachidanio rerio. This structure supersedes the now removed PDB entry 5c3v. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ATP, CA Gene: pip5k1aa, pip5k1a (Brachidanio rerio) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Signaling molecule phosphatidylinositol 4,5-bisphosphate is produced primarily by phosphatidylinositol 4-phosphate 5-kinase (PIP5K). PIP5K is essential for the development of the human neuronal system, which has been exemplified by a recessive genetic disorder, lethal congenital contractural syndrome type 3, caused by a single aspartate-to-asparagine mutation in the kinase domain of PIP5Kgamma. So far, the exact role of this aspartate residue has yet to be elucidated. In this work, we conducted structural, functional and computational studies on a zebrafish PIP5Kalpha variant with a mutation at the same site. Compared with the structure of the wild-type (WT) protein in the ATP-bound state, the ATP-associating glycine-rich loop of the mutant protein was severely disordered and the temperature factor of ATP was significantly higher. Both observations suggest a greater degree of disorder of the bound ATP, whereas neither the structure of the catalytic site nor the Km toward ATP was substantially affected by the mutation. Microsecond molecular dynamics simulation revealed that negative charge elimination caused by the mutation destabilized the involved hydrogen bonds and affected key electrostatic interactions in the close proximity of ATP. Taken together, our data indicated that the disease-related aspartate residue is a key node in the interaction network crucial for effective ATP binding. This work provides a paradigm of how a subtle but critical structural perturbation caused by a single mutation at the ATP-binding site abolishes the kinase activity, emphasizing that stabilizing substrate in a productive conformational state is crucial for catalysis. Structural insights into lethal contractural syndrome type 3 (LCCS3) caused by a missense mutation of PIP5Kgamma.,Zeng X, Uyar A, Sui D, Donyapour N, Wu D, Dickson A, Hu J Biochem J. 2018 Jul 26;475(14):2257-2269. doi: 10.1042/BCJ20180326. PMID:29959184 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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