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Related Concept Videos

Phosphoinositides and PIPs01:42

Phosphoinositides and PIPs

Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
Lipids as Anchors01:32

Lipids as Anchors

In the plasma membrane, the lipids forming the bilayer can also act as an anchor to tether proteins to the membrane. The three main types of lipid anchors found in eukaryotes are – prenyl groups, fatty acyl groups, and glycosylphosphatidylinositol or GPI groups. Prenyl and fatty acyl groups act as anchors on the cytosolic surface of the membrane, whereas GPI anchors proteins on the extracellular side.
The carboxy-terminal of most of the prenylated proteins, such as Ras proteins, contains the...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
IP3/DAG Signaling Pathway01:11

IP3/DAG Signaling Pathway

Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the  phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and produces two-second...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...

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Related Experiment Video

Updated: May 13, 2026

PIP-on-a-chip: A Label-free Study of Protein-phosphoinositide Interactions
10:58

PIP-on-a-chip: A Label-free Study of Protein-phosphoinositide Interactions

Published on: July 27, 2017

Structural basis for high-affinity inhibitor binding to lipid kinases PIP4K2A and PIP4K2B.

Zunyu He1, Song Chen1, Fabrizio Micheli2

  • 1Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520, USA.

Acta Crystallographica. Section D, Structural Biology
|May 12, 2026
PubMed
Summary

Researchers elucidated the structural basis for differential inhibition of phosphatidylinositol 5-phosphate 4-kinases (PIP4Ks). Understanding these lipid kinase structures aids in developing dual α/β inhibitors for therapeutic applications.

Keywords:
PIP4Kinhibitorslipid kinasesselectivitystructured water

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A Liposome Membrane Permeability Assay for Investigating the Effects of Phosphatidylinositol Phosphate Groups on Membranotropic Action of Venom PLA2
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A Liposome Membrane Permeability Assay for Investigating the Effects of Phosphatidylinositol Phosphate Groups on Membranotropic Action of Venom PLA2

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Characterization at the Molecular Level using Robust Biochemical Approaches of a New Kinase Protein
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Characterization at the Molecular Level using Robust Biochemical Approaches of a New Kinase Protein

Published on: June 30, 2019

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Last Updated: May 13, 2026

PIP-on-a-chip: A Label-free Study of Protein-phosphoinositide Interactions
10:58

PIP-on-a-chip: A Label-free Study of Protein-phosphoinositide Interactions

Published on: July 27, 2017

A Liposome Membrane Permeability Assay for Investigating the Effects of Phosphatidylinositol Phosphate Groups on Membranotropic Action of Venom PLA2
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Characterization at the Molecular Level using Robust Biochemical Approaches of a New Kinase Protein
11:23

Characterization at the Molecular Level using Robust Biochemical Approaches of a New Kinase Protein

Published on: June 30, 2019

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Phosphatidylinositol 5-phosphate 4-kinases (PIP4Ks) are lipid kinases crucial for cellular processes.
  • Mammalian PIP4K isoforms (α and β) are implicated in metabolism, immunity, and cancer.
  • Existing inhibitors show preferential potency for PIP4Kα over PIP4Kβ, limiting therapeutic potential.

Purpose of the Study:

  • To determine the crystal structure of PIP4Kα in complex with a dual inhibitor.
  • To elucidate the structural basis for isoform-selective inhibitor binding in PIP4Ks.
  • To provide a framework for designing improved PIP4K inhibitors with balanced isoform activity.

Main Methods:

  • X-ray crystallography of PIP4Kα complexed with inhibitor 422A.
  • Structural analysis and comparison with PIP4Kα-selective inhibitor BAY-091.
  • Comparative structural analysis of inhibitor binding pockets.

Main Results:

  • The crystal structure of PIP4Kα with dual inhibitor 422A revealed a water-mediated interaction critical for binding.
  • This interaction constrains inhibitor orientation and stabilizes a high-affinity binding mode.
  • Deeper pocket penetration enhances PIP4Kα binding but presents steric challenges for PIP4Kβ.

Conclusions:

  • Structural determinants of isoform-dependent inhibitor binding within the PIP4K family were identified.
  • A water-mediated interaction is key to the binding mode of dual inhibitor 422A.
  • Findings provide a basis for structure-guided optimization of PIP4K inhibitors for balanced isoform activity.