Tyrosine kinase receptor

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<StructureSection load='6p11' size='340' side='right' caption='Human TRK-A kinase domain complex with inhibitor, MPD and sulfate (PDB code [[6p11]])' scene=''>
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<StructureSection load='4yne' size='340' side='right' caption='Human TRK-A kinase domain complex with inhibitor, glycerol and sulfate (PDB code [[4yne]])' scene=''>
== Function ==
== Function ==
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'''Tyrosine kinase receptor''' or '''high affinity nerve growth factor receptor''' (TRK-A) play an important role in cellular processes like growth, motility, differentiation and metabolism<ref>PMID:29455648</ref>. Nerve growth factor (NGF) is a neutrotrophin which binds with high affinity to TRK. The binding of NGF to TRK-A activates the latter which undergoes dimerization and autophosphorylation at several Tyr residues that selectively trigger activity in several intercellular signaling pathways via binding of specific effector proteins<ref>PMID:24668471</ref>. There are 3 members to the TRK family: '''TRK-A''', '''TRK-B''' and '''TRK-C'''. All of them bind preferentially - NGF, neurotrophin-4, Brain-Derived Neurotrophic Factor (BDNF), and neurotrophin-3. See also [[High affinity nerve growth factor receptor]] and [[Neurotrophin]].
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'''Tyrosine kinase receptor''' or '''high affinity nerve growth factor receptor''' (TRK-A) play an important role in cellular processes like growth, motility, differentiation and metabolism<ref>PMID:29455648</ref>. Nerve growth factor (NGF) is a neutrotrophin which binds with high affinity to TRK. The binding of NGF to TRK-A activates the latter which undergoes dimerization and autophosphorylation at several Tyr residues that selectively trigger activity in several intercellular signaling pathways via binding of specific effector proteins<ref>PMID:24668471</ref>. There are 3 members to the TRK family: '''TRK-A''', '''TRK-B''' and '''TRK-C'''. All of them bind preferentially - NGF, neurotrophin-4, Brain-Derived Neurotrophic Factor (BDNF), and neurotrophin-3.
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*'''Trk-C''' is involved in the biology favourable neuroblastomas<ref>PMID:9516852</ref>.
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*'''Alk tyrosine kinase receptor''' is expressed in neurons of the central nervous system signaling growth and differentiation of neurons<ref>PMID:15226403</ref>.
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*'''RET tyrosine kinase receptor''' (Rearranged during transfection) plays a role in the development of the central and peripheral nervous systems<ref>PMID:32993133</ref>.
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*'''MuSK tyrosine kinase receptor''' (muscle-specific kinase) plays a role in signaling at the formation of neuromuscular junctions<ref>PMID:23467009</ref>.
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See also:
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*[[High affinity nerve growth factor receptor]]
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*[[Neurotrophin]].
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*[[Receptor tyrosine kinases]]
== Disease ==
== Disease ==
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== Structural highlights ==
== Structural highlights ==
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TRK-A contains an extracellular ligand binding domain (LBD), a transmembrane helix and an intracellular region which contains the kinase domain. The kinase domain (PDB code [[4yne]]) contains the tripeptide DFG which flips out in TRK-A inactivated form. <scene name='83/839914/Cv/3'>Inhibitor binding site</scene> (PDB code [[4yne]]). Water molecules are shown as red spheres. The structure of the complex of TRK-A with the phenylpyrrolidine derivative shows the inhibitor forming hydrogen bonds to Met620 and Lys572 residues and π-π interactions of it with Phe617 and Phe 698 <ref>PMID:26005534</ref>.
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TRK-A contains an extracellular ligand binding domain (LBD), a transmembrane helix and an intracellular region which contains the kinase domain. The kinase domain (PDB code [[4yne]]) contains the tripeptide DFG which flips out in TRK-A inactivated form. <scene name='83/839914/Cv/7'>Inhibitor binding site</scene> (PDB code [[4yne]]). Water molecules are shown as red spheres. The structure of the complex of TRK-A with the phenylpyrrolidine derivative shows the inhibitor forming hydrogen bonds to Met620 and Lys572 residues and π-π interactions of it with Phe617 and Phe 698 <ref>PMID:26005534</ref>.
The <scene name='83/839914/Cv/4'>complex between TRK-A and the nerve growth factor</scene> (PDB code [[2ifg]]) is a 2:2 dimer. The C-terminal immunoglobulin-like domain interacts with the NGF<ref>PMID:17196528</ref>. The extracellular domain of TRK-A contains <scene name='83/839914/Cv/5'>3 Leu-rich regions</scene> flanked by <scene name='83/839914/Cv/6'>Cys-rich regions</scene> (in yellow), 2 immunoglobulin-like domains and the nerve growth factor (NGF) binding domain.
The <scene name='83/839914/Cv/4'>complex between TRK-A and the nerve growth factor</scene> (PDB code [[2ifg]]) is a 2:2 dimer. The C-terminal immunoglobulin-like domain interacts with the NGF<ref>PMID:17196528</ref>. The extracellular domain of TRK-A contains <scene name='83/839914/Cv/5'>3 Leu-rich regions</scene> flanked by <scene name='83/839914/Cv/6'>Cys-rich regions</scene> (in yellow), 2 immunoglobulin-like domains and the nerve growth factor (NGF) binding domain.
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</StructureSection>
 
== 3D Structures tyrosine kinase receptor ==
== 3D Structures tyrosine kinase receptor ==
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Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
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[[Tyrosine kinase receptor 3D structures]]
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{{#tree:id=OrganizedByTopic|openlevels=0|
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*Tyrosine kinase receptor-A or high affinity nerve growth factor receptor; Domains – extracellular 36-382; LBD 285-380; transmembrane 410-447; kinase 498-796
 
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**[[1he7]] – hTRK-A LBD domain – human <BR />
 
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**[[4crp]] – hTRK-A LBD domain (mutant) – NMR<br />
 
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**[[2ifg]] – hTRK-A extracellular domain + b-nerve growth factor <BR />
 
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**[[4gt5]], [[4f0i]]] – hTRK-A kinase domain<BR />
 
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**[[5kvt]], [[6pl1]], [[6npt]], [[6nsp]], [[6nss]], [[5wr7]], [[6d1y]], [[6d1z]], [[6pmc]], [[6iqn]], [[6pl2]], [[6pl3]], [[6pma]], [[6pmb]], [[6pme]], [[5kmj]], [[5kmk]], [[5kmm]], [[5kmn]], [[5kmo]], [[4aoj]], [[4pmm]], [[4pmp]], [[4pms]], [[4pmt]], [[4yps]], [[5h3q]], [[5i8a]], [[5kmi]], [[5kml]], [[6d20]], [[6dkb]], [[6dkg]], [[6dki]], [[6j5l]], [[5jfs]], [[5jfv]], [[5jfw]], [[5jfx]], [[4yne]], [[6dkw]] – hTRK-A kinase domain + inhibitor<BR />
 
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**[[2n90]] – hTRK-A transmembrane domain - NMR <BR />
 
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*TRK-B or BDNF/NT-3 growth factor receptor
 
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**[[1wwb]] – hTRK-B LBD domain <BR />
 
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**[[1hcf]] – hTRK-B LBD domain + neutrotrophin-4<BR />
 
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**[[5mo9]] – hTRK-B LBD domain + antibody<BR />
 
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**[[4asz]] – hTRK-B kinase domain<BR />
 
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**[[4at3]], [[4at4]], [[4at5]] – hTRK-B kinase domain + inhibitor<BR />
 
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*TRK-C or NT-3 growth factor receptor
 
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**[[1wwc]], [[4pbv]] – hTRK-C LBD domain (mutant)<BR />
 
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**[[4pbv]], [[4pbw]] – hTRK-C extracellular domain (mutant) + tyrosine phosphatase s<BR />
 
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**[[3v5q]], [[4ymj]], [[6kzc]], [[6kzd]] – hTRK-C kinase domain + inhibitor<BR />
 
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}}
 
== References ==
== References ==
<references/>
<references/>
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</StructureSection>
[[Category:Topic Page]]
[[Category:Topic Page]]

Current revision

Human TRK-A kinase domain complex with inhibitor, glycerol and sulfate (PDB code 4yne)

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Proteopedia Page Contributors and Editors (what is this?)

Michal Harel, Alexander Berchansky

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