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Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

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Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
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Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
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Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
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When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
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Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...
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Updated: Apr 11, 2026

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The Disordered JM Motif in RTKs Promotes Classical DFGout Conformation Formation via the Dynamic Effect.

Xiaohui Chen1, Hao Wang1, Wenjian Li1

  • 1Research Center for Pharmacoinformatics, College of Pharmacy, Harbin Medical University, Harbin 150081, China.

Journal of Chemical Information and Modeling
|April 10, 2026
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Summary

The juxtamembrane (JM) motif in receptor tyrosine kinases (RTKs) dynamically promotes classical DFGout conformations, enhancing type II inhibitor binding. This finding aids the structure-based design of selective anticancer drugs.

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Pharmacology

Background:

  • Receptor tyrosine kinases (RTKs) are key anticancer targets.
  • Selective type II inhibitors target RTKs' DFGout conformations.
  • Scarcity of classical DFGout structures hinders inhibitor design.

Purpose of the Study:

  • Investigate the impact of the juxtamembrane (JM) motif on RTK DFGout conformations.
  • Explore how the JM motif influences inhibitor binding to VEGFR2.
  • Determine if the JM motif's role extends to other RTKs.

Main Methods:

  • Extensive molecular dynamics (MD) simulations.
  • Analysis of DFG motif conformational space.
  • Investigating JM motif dynamics and interactions within the kinase domain.

Main Results:

  • The disordered JM motif in VEGFR2 is dynamic, forming transient contacts.
  • JM motif shifts DFGout populations towards classical conformations.
  • JM motif promotes classical DFGout conformations in other RTKs.

Conclusions:

  • JM motif dynamics are crucial for enabling classical DFGout conformations.
  • This provides structural insights into JM motif's regulation of inhibitor binding.
  • JM motif's role offers opportunities for designing highly selective type II RTK inhibitors.