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4asz

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Revision as of 11:42, 5 August 2016

THE CRYSTAL STRUCTURES OF TRKA AND TRKB SUGGEST KEY REGIONS FOR ACHIEVING SELECTIVE INHIBITION

Structural highlights

4asz is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Related:	1hcf, 1wwb, 4at3, 4at4, 4at5, 4f0i
Activity:	Receptor protein-tyrosine kinase, with EC number 2.7.10.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[NTRK2_HUMAN] Defects in NTRK2 are the cause of obesity hyperphagia and developmental delay (OHPDD) [MIM:613886]. OHPDD is a disorder characterized by early-onset obesity, hyperphagia, and severe developmental delay in motor function, speech, and language.^[1]

Function

[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.^[2]

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^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Yeo GS, Connie Hung CC, Rochford J, Keogh J, Gray J, Sivaramakrishnan S, O'Rahilly S, Farooqi IS. A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat Neurosci. 2004 Nov;7(11):1187-9. Epub 2004 Oct 24. PMID:15494731 doi:10.1038/nn1336
↑ Yeo GS, Connie Hung CC, Rochford J, Keogh J, Gray J, Sivaramakrishnan S, O'Rahilly S, Farooqi IS. A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat Neurosci. 2004 Nov;7(11):1187-9. Epub 2004 Oct 24. PMID:15494731 doi:10.1038/nn1336
↑ Bertrand T, Kothe M, Liu J, Dupuy A, Rak A, Berne PF, Davis S, Gladysheva T, Valtre C, Crenne JY, Mathieu M. The Crystal Structures of TrkA and TrkB Suggest Key Regions for Achieving Selective Inhibition. J Mol Biol. 2012 Aug 16. PMID:22902478 doi:10.1016/j.jmb.2012.08.002

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4asz"

@@ Line 1: / Line 1: @@
 ==THE CRYSTAL STRUCTURES OF TRKA AND TRKB SUGGEST KEY REGIONS FOR ACHIEVING SELECTIVE INHIBITION==
 <StructureSection load='4asz' size='340' side='right' caption='[[4asz]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4asz]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ASZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ASZ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4asz]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ASZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ASZ FirstGlance]. <br>
 </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1hcf|1hcf]], [[1wwb|1wwb]], [[4at3|4at3]], [[4at4|4at4]], [[4at5|4at5]], [[4f0i|4f0i]]</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4asz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4asz OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4asz RCSB], [http://www.ebi.ac.uk/pdbsum/4asz PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4asz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4asz OCA], [http://pdbe.org/4asz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4asz RCSB], [http://www.ebi.ac.uk/pdbsum/4asz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4asz ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 19: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4asz" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Receptor protein-tyrosine kinase]]
 [[Category: Berne, P F]]

4asz

From Proteopedia

Revision as of 11:42, 5 August 2016

THE CRYSTAL STRUCTURES OF TRKA AND TRKB SUGGEST KEY REGIONS FOR ACHIEVING SELECTIVE INHIBITION

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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