View source for 6pmc


==TRK-A IN COMPLEX WITH LIGAND 1a==
<StructureSection load='6pmc' size='340' side='right'caption='[[6pmc]], [[Resolution|resolution]] 2.19&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6pmc]] 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=6PMC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PMC 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]] 2.19&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OQJ:~{N}-[6-[(5-chloranyl-2-methoxy-phenyl)carbamoylamino]-1,3-benzothiazol-2-yl]benzamide'>OQJ</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</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=6pmc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pmc OCA], [https://pdbe.org/6pmc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pmc RCSB], [https://www.ebi.ac.uk/pdbsum/6pmc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pmc ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/NTRK1_HUMAN NTRK1_HUMAN] Defects in NTRK1 are a cause of congenital insensitivity to pain with anhidrosis (CIPA) [MIM:[https://omim.org/entry/256800 256800]. CIPA is characterized by a congenital insensitivity to pain, anhidrosis (absence of sweating), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. This rare autosomal recessive disorder is also known as congenital sensory neuropathy with anhidrosis or hereditary sensory and autonomic neuropathy type IV or familial dysautonomia type II.<ref>PMID:8696348</ref> <ref>PMID:10090906</ref> <ref>PMID:10330344</ref> <ref>PMID:10233776</ref> <ref>PMID:10861667</ref> <ref>PMID:10982191</ref> <ref>PMID:10567924</ref> <ref>PMID:11310631</ref> <ref>PMID:11159935</ref> <ref>PMID:22302274</ref>   Defects in NTRK1 are a cause of thyroid papillary carcinoma (TPC) [MIM:[https://omim.org/entry/188550 188550]. TPC is a common tumor of the thyroid that typically arises as an irregular, solid or cystic mass from otherwise normal thyroid tissue. Papillary carcinomas are malignant neoplasm characterized by the formation of numerous, irregular, finger-like projections of fibrous stroma that is covered with a surface layer of neoplastic epithelial cells. Note=Chromosomal aberrations involving NTRK1 are found in thyroid papillary carcinomas. Translocation t(1;3)(q21;q11) with TFG generates the TRKT3 (TRK-T3) transcript by fusing TFG to the 3'-end of NTRK1; a rearrangement with TPM3 generates the TRK transcript by fusing TPM3 to the 3'-end of NTRK1; an intrachromosomal rearrangement that links the protein kinase domain of NTRK1 to the 5'-end of the TPR gene forms the fusion protein TRK-T1. TRK-T1 is a 55 kDa protein reacting with antibodies against the C-terminus of the NTRK1 protein.
== Function ==
[https://www.uniprot.org/uniprot/NTRK1_HUMAN NTRK1_HUMAN] Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand, it can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival. Upon dimeric NGF 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 driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors.<ref>PMID:1850821</ref> <ref>PMID:1849459</ref> <ref>PMID:8325889</ref> <ref>PMID:8155326</ref> <ref>PMID:11244088</ref> <ref>PMID:15488758</ref>   Isoform TrkA-III is resistant to NGF, constitutively activates AKT1 and NF-kappa-B and is unable to activate the Ras-MAPK signaling cascade. Antagonizes the anti-proliferative NGF-NTRK1 signaling that promotes neuronal precursors differentiation. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed.<ref>PMID:1850821</ref> <ref>PMID:1849459</ref> <ref>PMID:8325889</ref> <ref>PMID:8155326</ref> <ref>PMID:11244088</ref> <ref>PMID:15488758</ref> 
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== Publication Abstract from PubMed ==
In silico virtual screening followed by in vitro biochemical, biophysical, and cellular screening resulted in the identification of distinctly different hTrkA kinase domain inhibitor scaffolds. X-ray structural analysis of representative inhibitors bound to hTrkA kinase domain defined the binding mode and rationalized the mechanism of action. Preliminary assessment of the sub-type selectivity against the closest hTrkB isoform, and early ADME guided the progression of select inhibitor leads in the screening cascade. The possibility of the actives sustaining to known hTrkA resistance mutations assessed in silico offers initial guidance into the required multiparametric lead optimization to arrive at a clinical candidate.

Synthetic inhibitor leads of human tropomyosin receptor kinase A (hTrkA).,Subramanian G, Vairagoundar R, Bowen SJ, Roush N, Zachary T, Javens C, Williams T, Janssen A, Gonzales A RSC Med Chem. 2020 Jan 10;11(3):370-377. doi: 10.1039/c9md00554d. eCollection , 2020 Mar 1. PMID:33479642<ref>PMID:33479642</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6pmc" style="background-color:#fffaf0;"></div>

==See Also==
*[[High affinity nerve growth factor receptor|High affinity nerve growth factor receptor]]
*[[Tyrosine kinase receptor 3D structures|Tyrosine kinase receptor 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Brown DG]]
[[Category: Subramanian G]]