Neurotensin receptor: Difference between revisions
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New page: <StructureSection load='4GRV' size='350' side='right' caption='An interactive view of the class A GPCR, NTSR1 (blue). This protein gets its activity from binding to the 13 amino acid ligan... |
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<StructureSection load=' | {{BAMBED | ||
|DATE=June 14, 2016 | |||
|OLDID=2607459 | |||
|BAMBEDDOI=10.1002/bmb.21026 | |||
}} | |||
<StructureSection load='' size='350' side='right' caption='An interactive view of the class A GPCR, NTSR1 (blue). This protein gets its activity from binding to the 13 amino acid ligand, NTS (red). (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])' scene='72/721548/Whole_protein_no_t4l/8'> | |||
==Neurotensin Receptor (NTSR1)== | ==Neurotensin Receptor (NTSR1)== | ||
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The ligand for NTSR1 is the 13 amino acid peptide, neurotensin (NTS)<ref name="SONT">PMID:23051748</ref>, and the majority of the effects of NTS are mediated through NTSR1<ref name="SONT"/>. NTS has a variety of biological activities including a role in the '''[https://en.wikipedia.org/wiki/Leptin leptin]''' signaling pathways <ref name="Mice">PMID: 20211191</ref>, tumor growth <ref name="cancer">PMID:16887236</ref>, and '''[https://en.wikipedia.org/wiki/Dopamine dopamine]''' regulation <ref name="Schizophrenia">PMID:22596253</ref>. NTSR1 was crystallized bound with a C-terminal portion of its tridecapeptide '''[https://en.wikipedia.org/wiki/Ligand ligand]''', <scene name='72/721548/Neurotensin/7'>NTS(8-13)</scene>. The shortened ligand was used because of oits higher potency and efficacy than its full-length counterpart<ref name="SONT"/>. | The ligand for NTSR1 is the 13 amino acid peptide, neurotensin (NTS)<ref name="SONT">PMID:23051748</ref>, and the majority of the effects of NTS are mediated through NTSR1<ref name="SONT"/>. NTS has a variety of biological activities including a role in the '''[https://en.wikipedia.org/wiki/Leptin leptin]''' signaling pathways <ref name="Mice">PMID: 20211191</ref>, tumor growth <ref name="cancer">PMID:16887236</ref>, and '''[https://en.wikipedia.org/wiki/Dopamine dopamine]''' regulation <ref name="Schizophrenia">PMID:22596253</ref>. NTSR1 was crystallized bound with a C-terminal portion of its tridecapeptide '''[https://en.wikipedia.org/wiki/Ligand ligand]''', <scene name='72/721548/Neurotensin/7'>NTS(8-13)</scene>. The shortened ligand was used because of oits higher potency and efficacy than its full-length counterpart<ref name="SONT"/>. | ||
A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] that leads to the activation of the intracellular G protein. Currently, only the structure of the active form of NTSR1 is known, making the transition between the active and inactive states difficult to study.<ref name="SONT"/> | A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] that leads to the activation of the intracellular G protein. Currently, only the structure of the active form of NTSR1 is known, making the transition between the active and inactive states difficult to study.<ref name="SONT"/> | ||
*'''Neurotensin receptor 1''' is involved in the regulation of blood presure, body temperature, weight and response to pain<ref >PMID:31243364</ref> | |||
*'''Neurotensin receptor 3''' may serve as a scavenger receptor to eliminate neutotensin from the extracellular fluid and trigger its degradation<ref >PMID:11257441</ref> | |||
See also [[Transmembrane (cell surface) receptors]] | |||
== Neurotensin == | == Neurotensin == | ||
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== Structure == | == Structure == | ||
Like other G protein-coupled receptors, NTSR1 is composed of 3 distinct regions. An <scene name='72/727765/Overall_structure/5'>extracellular binding site</scene> where neurotensin binds and causes a conformational change of the protein. A region containing <scene name=' | Like other G protein-coupled receptors, NTSR1 is composed of 3 distinct regions. An <scene name='72/727765/Overall_structure/5'>extracellular binding site</scene> where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='73/733990/Overall/1'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Lastly, an intracellular region that when activated by a conformational change in the protein activates a [https://en.wikipedia.org/wiki/G_protein G-protein] associated with this receptor. | ||
The <scene name='72/721547/Hydrophobic_binding_pocket/6'>hydrophobic binding pocket</scene> in NTSR1 is located at the top of the protein (Figure 1). NTSR1 also contains an '''[https://en.wikipedia.org/wiki/Allosteric_regulation allosteric]''' <scene name='72/721548/Na_bind_pocket/13'>sodium binding pocket</scene>, which is located directly beneath the ligand binding pocket and the two pockets, which are separated by the residue <scene name='72/721548/Trp321/1'>Trp321</scene><ref name="SPGP">PMID:26205105</ref>. NTSR1 has been mutated to exist in both <scene name='72/721548/Ntsr1-elf/6'>active</scene> and <scene name='72/721547/Ntsr1-gw5/8'>active-like</scene> states. | The <scene name='72/721547/Hydrophobic_binding_pocket/6'>hydrophobic binding pocket</scene> in NTSR1 is located at the top of the protein (Figure 1). NTSR1 also contains an '''[https://en.wikipedia.org/wiki/Allosteric_regulation allosteric]''' <scene name='72/721548/Na_bind_pocket/13'>sodium binding pocket</scene>, which is located directly beneath the ligand binding pocket and the two pockets, which are separated by the residue <scene name='72/721548/Trp321/1'>Trp321</scene><ref name="SPGP">PMID:26205105</ref>. NTSR1 has been mutated to exist in both <scene name='72/721548/Ntsr1-elf/6'>active</scene> and <scene name='72/721547/Ntsr1-gw5/8'>active-like</scene> states. | ||
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[[Image: Meclinerant.jpg |200 px|right|thumb|Figure 4: Meclinerant: An inhibitor of NTSR1 found to enhance selectivity of radiotherapy in cancer treatment.]] NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines making it a promising cancer drug target. It is prevalent in [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types.<ref name="Valerie">PMID:21903767</ref> NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation.<ref name="Valerie"/> These all result in increased DNA synthesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy], which uses radiation to target malignant cells. NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which inhibits proliferation and prosurvival of cancer cells. Combination treatment of radiation and meclinerant provides selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Kisfalvi">PMID:19679549</ref> | [[Image: Meclinerant.jpg |200 px|right|thumb|Figure 4: Meclinerant: An inhibitor of NTSR1 found to enhance selectivity of radiotherapy in cancer treatment.]] NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines making it a promising cancer drug target. It is prevalent in [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types.<ref name="Valerie">PMID:21903767</ref> NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation.<ref name="Valerie"/> These all result in increased DNA synthesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy], which uses radiation to target malignant cells. NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which inhibits proliferation and prosurvival of cancer cells. Combination treatment of radiation and meclinerant provides selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Kisfalvi">PMID:19679549</ref> | ||
== | ==Student Contributors== | ||
< | Allie Cotter | ||
Danny Cotter | |||
Andrew Koelper | |||
Brent Waibel | |||
==3D structures of neurotensin receptor== | |||
</StructureSection> | |||
==3D structures of neurotensin receptor== | |||
Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}} | |||
{{#tree:id=OrganizedByTopic|openlevels=0| | |||
* Neurotensin receptor 1 | |||
**[[6os9]], [[6osa]] - hNTR1 (mutant) in GI1 complex – human – Cryo EM<br /> | |||
**[[6pwc]] - hNTR1 + neurotensin peptide + arrestin + antibody – Cryo EM<br /> | |||
**[[7ul2]] - hNTR1 + nanobody – Cryo EM<br /> | |||
**[[6up7]] - hNTR1 + peptide + arrestin – Cryo EM<br /> | |||
**[[6z66]] - rNTR1 - rat<br /> | |||
**[[5t04]], [[6z4v]] - rNTR1 + peptide - rat<br /> | |||
**[[4xee]], [[4xes]], [[4grv]] - rNTR1 + neurotensin peptide<br /> | |||
**[[3zev]], [[4buo]], [[4bv0]], [[4bwb]] - rNTR1 (mutant) + neurotensin peptide<br /> | |||
**[[7l0p]], [[7l0q]], [[7l0r]], [[7l0s]] - rNTR1 (mutant) + neurotensin peptide + Gi – Cryo EM<br /> | |||
**[[8fmz]], [[8fn0]] - rNTR1 (mutant) + neurotensin peptide + Gi + scfV – Cryo EM<br /> | |||
**[[8fn1]] - rNTR1 + neurotensin peptide + Gi + scfV – Cryo EM<br /> | |||
**[[6z4q]], [[6z4s]], [[6z8n]], [[6za8]], [[6zin]] - rNTR1 + agonist<br /> | |||
**[[6yvr]] - rNTR1 + peptide agonist<br /> | |||
* Neurotensin receptor 3 (sortilin) | |||
**[[6eho]] – hNTR3 Vps10P domain (mutant) <br /> | |||
**[[4po7]] – hNTR3 Vps10P domain + neurotensin/neuromedin N peptide<br /> | |||
**[[3f6k]] – hNTR3 Vps10P domain + neurotensin peptide <br /> | |||
**[[4msl]] – hNTR3 Vps10P domain + ligand<br /> | |||
**[[6x3l]], [[6x48]], [[6x4h]] – hNTR3 Vps10P domain + inhibitor<br /> | |||
**[[4n7e]] – hNTR3 Vps10P domain (mutant) + inhibitor<br /> | |||
**[[5mrh]], [[5mri]] – hNTR3 Vps10P domain + triazolone<br /> | |||
**[[5nmr]], [[5nmt]], [[5nni]], [[5nnj]] – mNTR3 extracellular domain - mouse<br /> | |||
**[[5znn]] – mNTR3 Vps10P domain <br /> | |||
}} | |||
==Proteopedia Resources== | ==Proteopedia Resources== | ||
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[http://proteopedia.org/wiki/index.php/User:R._Jeremy_Johnson/CH462:Biochemistry_II_Butler_University Butler University Proteopedia Pages] | [http://proteopedia.org/wiki/index.php/User:R._Jeremy_Johnson/CH462:Biochemistry_II_Butler_University Butler University Proteopedia Pages] | ||
See also: | |||
*[[Receptor]] | |||
*[[Transmembrane (cell surface) receptors]] | |||
*[[G protein-coupled receptors]] | |||
== References == | |||
<references/> | |||
[[Category:Featured in BAMBED]] | |||
[[Category:Topic Page]] | |||