|1hcf, resolution 2.70Å ()|
|Related:||1wwb, 1b8m, 1b98|
CRYSTAL STRUCTURE OF TRKB-D5 BOUND TO NEUROTROPHIN-4/5
BACKGROUND: The binding of neurotrophin ligands to their respective Trk cellular receptors initiates intracellular signals essential for the growth and survival of neurons. The site of neurotrophin binding has been located to the fifth extracellular domain of the Trk receptor, with this region regulating both the affinity and specificity of Trk receptor:neurotrophin interaction. Neurotrophin function has been implicated in a number of neurological disorders, including Alzheimer's disease and Parkinson's disease. RESULTS: We have determined the 2.7 A crystal structure of neurotrophin-4/5 bound to the neurotrophin binding domain of its high-affinity receptor TrkB (TrkB-d5). As previously seen in the interaction of nerve growth factor with TrkA, neurotrophin-4/5 forms a crosslink between two spatially distant receptor molecules. The contacts formed in the TrkB-d5:neurotrophin-4/5 complex can be divided into a conserved area similar to a region observed in the TrkA-d5:NGF complex and a second site-unique in each ligand-receptor pair-formed primarily by the ordering of the neurotrophin N terminus. CONCLUSIONS: Together, the structures of the TrkB-d5:NT-4/5 and TrkA-d5:NGF complexes confirm a consistent pattern of recognition in Trk receptor:neurotrophin complex formation. In both cases, the N terminus of the neurotrophin becomes ordered only on complex formation. This ordering appears to be directed largely by the receptor surface, with the resulting complementary surfaces providing the main determinant of receptor specificity. These features provide an explanation both for the limited crossreactivity observed between the range of neurotrophins and Trk receptors and for the high-affinity binding associated with respective ligand-receptor pairs.
Specificity in Trk receptor:neurotrophin interactions: the crystal structure of TrkB-d5 in complex with neurotrophin-4/5., Banfield MJ, Naylor RL, Robertson AG, Allen SJ, Dawbarn D, Brady RL, Structure. 2001 Dec;9(12):1191-9. PMID:11738045
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[NTF4_HUMAN] Defects in NTF4 may be associated with susceptibility to primary open angle glaucoma type 1O (GLC1O) [MIM:613100]. A form of primary open angle glaucoma (POAG). POAG is characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. The disease is asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place.
[NTF4_HUMAN] Target-derived survival factor for peripheral sensory sympathetic neurons.
About this Structure
- Banfield MJ, Naylor RL, Robertson AG, Allen SJ, Dawbarn D, Brady RL. Specificity in Trk receptor:neurotrophin interactions: the crystal structure of TrkB-d5 in complex with neurotrophin-4/5. Structure. 2001 Dec;9(12):1191-9. PMID:11738045
- Robertson AG, Banfield MJ, Allen SJ, Dando JA, Mason GG, Tyler SJ, Bennett GS, Brain SD, Clarke AR, Naylor RL, Wilcock GK, Brady RL, Dawbarn D. Identification and structure of the nerve growth factor binding site on TrkA. Biochem Biophys Res Commun. 2001 Mar 23;282(1):131-41. PMID:11263982 doi:10.1006/bbrc.2001.4462
- Wiesmann C, Ultsch MH, Bass SH, de Vos AM. Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor. Nature. 1999 Sep 9;401(6749):184-8. PMID:10490030 doi:10.1038/43705
- Ultsch MH, Wiesmann C, Simmons LC, Henrich J, Yang M, Reilly D, Bass SH, de Vos AM. Crystal structures of the neurotrophin-binding domain of TrkA, TrkB and TrkC. J Mol Biol. 1999 Jul 2;290(1):149-59. PMID:10388563 doi:10.1006/jmbi.1999.2816