View source for 4at5


==CRYSTAL STRUCTURE OF TRKB KINASE DOMAIN IN COMPLEX WITH GW2580==
<StructureSection load='4at5' size='340' side='right'caption='[[4at5]], [[Resolution|resolution]] 1.71&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4at5]] 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=4AT5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4AT5 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]] 1.71&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MUJ:5-{3-METHOXY-4-[(4-METHOXYBENZYL)OXY]BENZYL}PYRIMIDINE-2,4-DIAMINE'>MUJ</scene></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=4at5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4at5 OCA], [https://pdbe.org/4at5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4at5 RCSB], [https://www.ebi.ac.uk/pdbsum/4at5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4at5 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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The Trk family of neurotrophin receptors, which includes the three highly homologous proteins TrkA, TrkB and TrkC, is strongly associated with central and peripheral nervous system processes. Trk proteins are also of interest in oncology, since Trk activation has been observed in several cancer types. While Trk kinases are attractive oncology targets, selectivity might be more of an issue than for other kinases due to potential CNS side effects if several Trk kinases are simultaneously targeted. In order to address this issue, we present here the first structures of human TrkA and TrkB kinase domains and three complexes between TrkB and Trk inhibitors. These structures reveal different conformations of the kinase domain and suggest new regions of selectivity among the Trk family.

The Crystal Structures of TrkA and TrkB Suggest Key Regions for Achieving Selective Inhibition.,Bertrand T, Kothe M, Liu J, Dupuy A, Rak A, Berne PF, Davis S, Gladysheva T, Valtre C, Crenne JY, Mathieu M J Mol Biol. 2012 Aug 16. PMID:22902478<ref>PMID:22902478</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4at5" style="background-color:#fffaf0;"></div>

==See Also==
*[[TrkB tyrosine kinase receptor|TrkB tyrosine kinase receptor]]
*[[Tyrosine kinase receptor|Tyrosine kinase receptor]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Berne PF]]
[[Category: Bertrand T]]
[[Category: Crenne JY]]
[[Category: Davis S]]
[[Category: Dupuy A]]
[[Category: Gladysheva T]]
[[Category: Kothe M]]
[[Category: Liu J]]
[[Category: Mathieu M]]
[[Category: Rak A]]
[[Category: Valtre C]]