5W2H

Crystal structure of the core catalytic domain of human inositol phosphate multikinase in complex with Ins(1,4,5)P3 and ADP

Summary for 5W2H

• Entry DOI: 10.2210/pdb5w2h/pdb
• Related: 5W2G 5W2I
• Descriptor: Inositol polyphosphate multikinase,Inositol polyphosphate multikinase, MAGNESIUM ION, ADENOSINE-5'-DIPHOSPHATE, ... (6 entities in total)
• Functional Keywords: kinase, inositol, inositol polyphosphate, phosphatidylinositol, specificity, transferase
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : Q8NFU5
• Total number of polymer chains: 1
• Total formula weight: 30418.34

Authors

Wang, H.,Shears, S.B. (deposition date: 2017-06-06, release date: 2017-09-13, Last modification date: 2023-10-04)

Primary citation

Wang, H.,Shears, S.B.
Structural features of human inositol phosphate multikinase rationalize its inositol phosphate kinase and phosphoinositide 3-kinase activities.
J. Biol. Chem., 292:18192-18202, 2017

PubMed Abstract: Human inositol phosphate multikinase (IPMK) critically contributes to intracellular signaling through its inositol-1,4,5-trisphosphate (Ins(1,4,5)P) 3-kinase and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P) 3-kinase activities. This catalytic profile is not conserved; orthologs from and are predominantly Ins(1,4,5)P 6-kinases, and the plant enzyme cannot phosphorylate PtdIns(4,5)P Therefore, crystallographic analysis of the yeast and plant enzymes, without bound inositol phosphates, do not structurally rationalize IPMK activities. Here, we present 1.6-Å resolution crystal structures of IPMK in complex with either Ins(1,4,5)P or PtdIns(4,5)P The Ins(1,4,5)P headgroup of PtdIns(4,5)P binds in precisely the same orientation as free Ins(1,4,5)P itself, indicative of evolutionary optimization of 3-kinase activities against both substrates. We report on nucleotide binding between the separate N- and C-lobes of IPMK. The N-lobe exhibits a remarkable degree of conservation with protein kinase A (root mean square deviation = 1.8 Å), indicating common ancestry. We also describe structural features unique to IPMK. First, we observed a constrained, horseshoe-shaped substrate pocket, formed from an α-helix, a 3 helix, and a recently evolved tri-proline loop. We further found IPMK activities rely on a preponderance of Gln residues, in contrast to the larger Lys and Arg residues in yeast and plant orthologs. These conclusions are supported by analyzing 14 single-site IPMK mutants, some of which differentially affect 3-kinase and 6-kinase activities. Overall, we structurally rationalize phosphorylation of Ins(1,4,5)P and PtdIns(4,5)P by IPMK.

PubMed: 28882892
DOI: 10.1074/jbc.M117.801845

Experimental method

X-RAY DIFFRACTION (1.9 Å)