View source for 1wwb


==LIGAND BINDING DOMAIN OF HUMAN TRKB RECEPTOR==
<StructureSection load='1wwb' size='340' side='right'caption='[[1wwb]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1wwb]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1WWB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1WWB FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1wwb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1wwb OCA], [https://pdbe.org/1wwb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1wwb RCSB], [https://www.ebi.ac.uk/pdbsum/1wwb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1wwb ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/NTRK2_HUMAN NTRK2_HUMAN] Defects in NTRK2 are the cause of obesity hyperphagia and developmental delay (OHPDD) [MIM:[https://omim.org/entry/613886 613886]. OHPDD is a disorder characterized by early-onset obesity, hyperphagia, and severe developmental delay in motor function, speech, and language.<ref>PMID:15494731</ref> 
== Function ==
[https://www.uniprot.org/uniprot/NTRK2_HUMAN NTRK2_HUMAN] Receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differentiation, and synapse formation and plasticity. Receptor for BDNF/brain-derived neurotrophic factor and NTF4/neurotrophin-4. Alternatively can also bind NTF3/neurotrophin-3 which is less efficient in activating the receptor but regulates neuron survival through NTRK2. Upon ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades. Through SHC1, FRS2, SH2B1, SH2B2 activates the GRB2-Ras-MAPK cascade that regulates for instance neuronal differentiation including neurite outgrowth. Through the same effectors controls the Ras-PI3 kinase-AKT1 signaling cascade that mainly regulates growth and survival. Through PLCG1 and the downstream protein kinase C-regulated pathways controls synaptic plasticity. Thereby, plays a role in learning and memory by regulating both short term synaptic function and long-term potentiation. PLCG1 also leads to NF-Kappa-B activation and the transcription of genes involved in cell survival. Hence, it is able to suppress anoikis, the apoptosis resulting from loss of cell-matrix interactions. May also play a role in neutrophin-dependent calcium signaling in glial cells and mediate communication between neurons and glia.<ref>PMID:15494731</ref> 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ww/1wwb_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1wwb ConSurf].
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== Publication Abstract from PubMed ==
The Trk receptors and their neurotrophin ligands control development and maintenance of the nervous system. The crystal structures of the ligand binding domain of TrkA, TrkB, and TrkC were solved and refined to high resolution. The domains adopt an immunoglobulin-like fold, but crystallized in all three instances as dimers with the N-terminal strand of each molecule replaced by the same strand of a symmetry-related mate. Models of the correctly folded domains could be constructed by changing the position of a single residue, and the resulting model of the binding domain of TrkA is essentially identical with the bound structure as observed in a complex with nerve growth factor. An analysis of the existing mutagenesis data for TrkA and TrkC in light of these structures reveals the structural reasons for the specificity among the Trk receptors, and explains the underpinnings of the multi-functional ligands that have been reported. The overall structure of all three domains belongs to the I-set of immunoglobulin-like domains, but shows several unusual features, such as an exposed disulfide bridge linking two neighboring strands in the same beta-sheet. For all three domains, the residues that deviate from the standard fingerprint pattern common to the I-set family fall in the region of the ligand binding site observed in the complex. Therefore, identification of these deviations in the sequences of other immunoglobulin-like domain-containing receptors may help to identify their ligand binding site even in the absence of structural or mutagenesis data.

Crystal structures of the neurotrophin-binding domain of TrkA, TrkB and TrkC.,Ultsch MH, Wiesmann C, Simmons LC, Henrich J, Yang M, Reilly D, Bass SH, de Vos AM J Mol Biol. 1999 Jul 2;290(1):149-59. PMID:10388563<ref>PMID:10388563</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
*[[TrkB tyrosine kinase receptor|TrkB tyrosine kinase receptor]]
*[[Tyrosine kinase receptor 3D structures|Tyrosine kinase receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bass SH]]
[[Category: De Vos AM]]
[[Category: Ultsch MH]]
[[Category: Wiesmann C]]