Crystal Structures of Neurotrophin Receptors Kinase Domain

Vitam Horm. 2017:104:1-18. doi: 10.1016/bs.vh.2016.10.001. Epub 2016 Nov 29.

Abstract

Neurotrophins and their receptors (Trk) play key roles in the development of the nervous system and in cell survival. Trk receptors are therefore attractive pharmacological targets for brain disorders as well as for cancers. While the druggability of the extracellular domain of the receptors, that specifically binds neurotrophins, is yet to be proven, the intracellular kinase domains are attractive targets for small-molecule binding. The recent crystal structures of the three isoforms of the Trk family, TrkA, TrkB, and TrkC have been described in their apo forms and in complex with potent and selective pan-Trk inhibitors. The description of the kinase domain of each of the isoforms will be discussed in their apo forms or bound to potent inhibitors of interest in cancer therapy. Nononcology indications and selectivity issues will also be discussed.

Keywords: Drug design; Inhibitors; Kinase; Pharmacology; Selectivity; Structure.

Publication types

  • Review

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Apoenzymes / chemistry
  • Apoenzymes / metabolism
  • Binding Sites
  • Catalytic Domain
  • Humans
  • Isoenzymes / chemistry
  • Isoenzymes / metabolism
  • Ligands
  • Membrane Glycoproteins / agonists
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / metabolism*
  • Models, Molecular*
  • Molecular Conformation
  • Nerve Growth Factors / chemistry
  • Nerve Growth Factors / metabolism
  • Phenylalanine / chemistry
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Receptor, trkA / agonists
  • Receptor, trkA / antagonists & inhibitors
  • Receptor, trkA / chemistry
  • Receptor, trkA / metabolism*
  • Receptor, trkB / agonists
  • Receptor, trkB / antagonists & inhibitors
  • Receptor, trkB / chemistry
  • Receptor, trkB / metabolism*
  • Receptor, trkC / agonists
  • Receptor, trkC / antagonists & inhibitors
  • Receptor, trkC / chemistry
  • Receptor, trkC / metabolism*
  • Structural Homology, Protein

Substances

  • Antineoplastic Agents
  • Apoenzymes
  • Isoenzymes
  • Ligands
  • Membrane Glycoproteins
  • NTRK1 protein, human
  • Nerve Growth Factors
  • Protein Kinase Inhibitors
  • Phenylalanine
  • Adenosine Triphosphate
  • Receptor, trkA
  • Receptor, trkB
  • Receptor, trkC
  • tropomyosin-related kinase-B, human