Structure of a human inositol 1,4,5-trisphosphate 3-kinase: Substrate binding reveals why it is not a phosphoinositide 3-kinase

Beatriz González, Michael J. Schell, Andrew J. Letcher, Dmitry B. Veprintsev, Robin F. Irvine, Roger L. Williams

Research output: Contribution to journalArticlepeer-review

Abstract

Mammalian cells produce a variety of inositol phosphates (InsPs), including Ins(1,4,5)P3 that serves both as a second messenger and as a substrate for inositol polyphosphate kinases (IPKs), which further phosphorylate it. We report the structure of an IPK, the human Ins(1,4,5)P3 3-kinase-A, both free and in complexes with substrates and products. This enzyme catalyzes transfer of a phosphate from ATP to the 3-OH of Ins(1,4,5)P 3, and its X-ray crystal structure provides a template for understanding a broad family of InsP kinases. The catalytic domain consists of three lobes. The N and C lobes bind ATP and resemble protein and lipid kinases, despite insignificant sequence similarity. The third lobe binds inositol phosphate and is a unique four-helix insertion in the C lobe. This lobe embraces all of the phosphates of Ins(1,4,5)P3 in a positively charged pocket, explaining the enzyme's substrate specificity and its inability to phosphorylate PtdIns(4,5)P2, the membrane-resident analog of Ins(1,4,5)P3.

Original languageEnglish (US)
Pages (from-to)689-701
Number of pages13
JournalMolecular cell
Volume15
Issue number5
DOIs
StatePublished - Sep 10 2004
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Structure of a human inositol 1,4,5-trisphosphate 3-kinase: Substrate binding reveals why it is not a phosphoinositide 3-kinase'. Together they form a unique fingerprint.

Cite this