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5mo9

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Revision as of 08:00, 3 April 2019

Structure of human TrkB receptor ligand binding domain in complex with the Fab frgment of antibody AB20

Structural highlights

5mo9 is a 3 chain structure with sequence from Human and Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:	NTRK2, TRKB (HUMAN)
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

Brain-derived neurotrophic factor (BDNF) is a central modulator of neuronal development and synaptic plasticity in the central nervous system. This renders the BDNF-modulated tropomyosin receptor kinase B (TrkB) a promising drug target to treat synaptic dysfunctions. Using GRowth factor-driven expansion and INhibition of NotCH (GRINCH) during maturation, the so-called GRINCH neurons were derived from human-induced pluripotent stem cells. These GRINCH neurons were used as model cells for pharmacologic profiling of two TrkB-agonistic antibodies, hereafter referred to as AB2 and AB20 In next-generation sequencing studies, AB2 and AB20 stimulated transcriptional changes, which extensively overlapped with BDNF-driven transcriptional modulation. In regard to TrkB phosphorylation, both AB2 and AB20 were only about half as efficacious as BDNF; however, with respect to the TrkB downstream signaling, AB2 and AB20 displayed increased efficacy values, providing a stimulation at least comparable to BDNF in respect to VGF transcription, as well as of AKT and cAMP response element-binding protein phosphorylation. In a complex structure of the TrkB-d5 domain with AB20, determined by X-ray crystallography, the AB20 binding site was found to be allosteric in regard to the BDNF binding site, whereas AB2 was known to act orthosterically with BDNF. In agreement with this finding, AB2 and AB20 acted synergistically at greater concentrations to drive TrkB phosphorylation. Although TrkB downstream signaling declined faster after pulse stimulation with AB20 than with AB2, AB20 restimulated TrkB phosphorylation more efficiently than AB2. In conclusion, both antibodies displayed some limitations and some benefits in regard to future applications as therapeutic agents.

Pharmaceutical Characterization of Tropomyosin Receptor Kinase B-Agonistic Antibodies on Human Induced Pluripotent Stem (hiPS) Cell-Derived Neurons.,Traub S, Stahl H, Rosenbrock H, Simon E, Florin L, Hospach L, Horer S, Heilker R J Pharmacol Exp Ther. 2017 Jun;361(3):355-365. doi: 10.1124/jpet.117.240184. Epub, 2017 Mar 28. PMID:28351853^[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
↑ Traub S, Stahl H, Rosenbrock H, Simon E, Florin L, Hospach L, Horer S, Heilker R. Pharmaceutical Characterization of Tropomyosin Receptor Kinase B-Agonistic Antibodies on Human Induced Pluripotent Stem (hiPS) Cell-Derived Neurons. J Pharmacol Exp Ther. 2017 Jun;361(3):355-365. doi: 10.1124/jpet.117.240184. Epub, 2017 Mar 28. PMID:28351853 doi:http://dx.doi.org/10.1124/jpet.117.240184

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5mo9"

@@ Line 1: / Line 1: @@
 ==Structure of human TrkB receptor ligand binding domain in complex with the Fab frgment of antibody AB20==
-<StructureSection load='5mo9' size='340' side='right' caption='[[5mo9]], [[Resolution|resolution]] 2.59&Aring;' scene=''>
+<StructureSection load='5mo9' size='340' side='right'caption='[[5mo9]], [[Resolution|resolution]] 2.59&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5mo9]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MO9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MO9 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5mo9]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MO9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MO9 FirstGlance]. <br>
-</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>
+</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NTRK2, TRKB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5mo9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mo9 OCA], [http://pdbe.org/5mo9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mo9 RCSB], [http://www.ebi.ac.uk/pdbsum/5mo9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mo9 ProSAT]</span></td></tr>
 </table>
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 5mo9" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[TrkB tyrosine kinase receptor|TrkB tyrosine kinase receptor]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
+[[Category: Lk3 transgenic mice]]
 [[Category: Receptor protein-tyrosine kinase]]
 [[Category: Hoerer, S]]

5mo9

From Proteopedia

Revision as of 08:00, 3 April 2019

Structure of human TrkB receptor ligand binding domain in complex with the Fab frgment of antibody AB20

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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