Sandbox Reserved 1176: Difference between revisions

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==Introduction==

[[Image:surfaceprotein.png |300 px|below|thumb|'''Figure 1'''.Top view of NTSR1 protein interacting with NTS ligand]]

Neurotensin receptor 1 (NTSR1) is a '''[https://en.wikipedia.org/wiki/G_protein%E2%80%93coupled_receptor G-protein coupled receptor (GPCR).]''' GPCRs are a class of proteins with an extracellular binding domain and 7 transmembrane helices found only in '''[https://en.wikipedia.org/wiki/Eukaryote. eukaryotes]''' that assist in propagating a cellular response. This is accomplished by the binding of molecules to the GPCR outside the cell,causing a '''[https://en.wikipedia.org/wiki/Conformational_change conformational change]''' and activating a '''[https://en.wikipedia.org/wiki/Signal_transduction signal transduction]''' pathway via '''[https://en.wikipedia.org/wiki/Second_messenger_system second messengers]''' such as '''[https://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphate cyclic AMP]''', '''[https://en.wikipedia.org/wiki/Inositol_trisphosphate inositol triphosphate]''', and '''[https://en.wikipedia.org/wiki/Diglyceride diacylglycerol]'''.<ref name="SPGP"/>. NTSR1 binds to 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>.Recently NTSR1 was crystallized bound with the C-terminus 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 it has a higher potency and efficacy than its full-length counterpart<ref name="SONT"/>. Class A GPCRs bind their ligands within the '''[https://en.wikipedia.org/wiki/Transmembrane_protein transmembrane]''' core in a ligand binding pocket. The <scene name='72/721547/Hydrophobic_binding_pocket/5'>ligand 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'>Na+ Binding Pocket</scene>. The Na+ binding pocket is located directly beneath the ligand binding pocket and the two pockets are separated by the residue ~~W321~~. <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. This has led to a greater understanding of the structure of NTSR1 and how the structure influences its function.

Neurotensin receptor 1 (NTSR1) is a '''[https://en.wikipedia.org/wiki/G_protein%E2%80%93coupled_receptor G-protein coupled receptor (GPCR).]''' GPCRs are a class of proteins with an extracellular binding domain and 7 transmembrane helices found only in '''[https://en.wikipedia.org/wiki/Eukaryote. eukaryotes]''' that assist in propagating a cellular response. This is accomplished by the binding of molecules to the GPCR outside the cell,causing a '''[https://en.wikipedia.org/wiki/Conformational_change conformational change]''' and activating a '''[https://en.wikipedia.org/wiki/Signal_transduction signal transduction]''' pathway via '''[https://en.wikipedia.org/wiki/Second_messenger_system second messengers]''' such as '''[https://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphate cyclic AMP]''', '''[https://en.wikipedia.org/wiki/Inositol_trisphosphate inositol triphosphate]''', and '''[https://en.wikipedia.org/wiki/Diglyceride diacylglycerol]'''.<ref name="SPGP"/>. NTSR1 binds to 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>.Recently NTSR1 was crystallized bound with the C-terminus 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 it has a higher potency and efficacy than its full-length counterpart<ref name="SONT"/>. Class A GPCRs bind their ligands within the '''[https://en.wikipedia.org/wiki/Transmembrane_protein transmembrane]''' core in a ligand binding pocket. The <scene name='72/721547/Hydrophobic_binding_pocket/5'>ligand 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'>Na+ Binding Pocket</scene>. The Na+ binding pocket is located directly beneath the ligand binding pocket and the two pockets are separated by the residue Trp321. <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. This has led to a greater understanding of the structure of NTSR1 and how the structure influences its function.

== Structure ==

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On the extracellular side of the protein is the

<scene name='72/721547/Hydrophobic_binding_pocket/5'>hydrophobic binding pocket</scene>.

One key residue in this pocket is a Phenylalanine at position 358, and its purpose is to take part in a network of hydrophobic stacking interactions. These interactions stabilize the Trp321 and Tyr324 residues allowing Tyr324 to interact with the C-terminal

One key residue in this pocket is a Phenylalanine at position 358, and its purpose is to take part in a network of hydrophobic stacking interactions. These interactions stabilize the Trp321 and Tyr324 residues allowing Tyr324 to interact with the '''[https://en.wikipedia.org/wiki/C-terminus C-terminal]'''

<scene name='72/721547/Ligand_protein_interactions/7'>Leu13 residue of the NTS ligand</scene>

via '''[https://en.wikipedia.org/wiki/Van_der_Waals_force Van der Waals interactions]''' .

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===Na+ Binding Pocket===

[[Image:Na+ Proteopedia Picture.png |300 px|left|thumb|Figure 2. Residues of collapsed sodium binding pocket. Trp321 (blue) sets the top of the pocket, where Ser362, Asp113, Thr156 and Asn365 (gray) are involved in hydrogen bonding interactions preventing the coordination of a Na+ ion.]]

[[Image:Na+ Proteopedia Picture.png |300 px|left|thumb|Figure 2. Residues of collapsed sodium binding pocket. Trp321 (blue) sets the top of the pocket, where Ser362, Asp113, Thr156 and Asn365 (gray) are involved in hydrogen bonding interactions preventing the coordination of a Na+ ion.]]

<scene name='72/721548/Trp321/1'>Trp321</scene>, which is positioned at the bottom of the <scene name='72/721547/Hydrophobic_binding_pocket/5'>hydrophobic binding pocket</scene>, sets the top of the <scene name='72/721548/Na_bind_pocket/12'> Na+ Binding Pocket</scene>. The Na+ ion binding pocket acts as a negative allosteric site for G protein activity <ref name="SPGP"/>. When Na+ enters the Na+ ion binding pocket, it coordinates with Asp95, Gln131, Ser135, and Asp113, decreasing the signaling activity of NTSR1 <ref name="SPGP"/>. When NTSR1 is in its active state, the Na+ ion binding pocket is collapsed, preventing the regulations of protein activity through a Na+ ion, as the Na+ ion is unable to be coordinated by a salt bridge to Asp113 (Figure 2). The side chain atoms of Asp113 form a '''[https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bond]''' network with Thr156, Ser361, Ser362, and Gln365 instead, which prevents the coordination of a Na+ ion<ref name ="SPGP"/> (Figure 2).

Sandbox Reserved 1176: Difference between revisions

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@@ Line 4: / Line 4: @@
 ==Introduction==
 [[Image:surfaceprotein.png |300 px|below|thumb|'''Figure 1'''.Top view of NTSR1 protein interacting with NTS ligand]]
-Neurotensin receptor 1 (NTSR1) is a '''[https://en.wikipedia.org/wiki/G_protein%E2%80%93coupled_receptor G-protein coupled receptor (GPCR).]''' GPCRs are a class of proteins with an extracellular binding domain and 7 transmembrane helices found only in '''[https://en.wikipedia.org/wiki/Eukaryote. eukaryotes]''' that assist in propagating a cellular response. This is accomplished by the binding of molecules to the GPCR outside the cell,causing a '''[https://en.wikipedia.org/wiki/Conformational_change conformational change]''' and activating a '''[https://en.wikipedia.org/wiki/Signal_transduction signal transduction]''' pathway via '''[https://en.wikipedia.org/wiki/Second_messenger_system second messengers]''' such as '''[https://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphate  cyclic AMP]''', '''[https://en.wikipedia.org/wiki/Inositol_trisphosphate  inositol triphosphate]''', and '''[https://en.wikipedia.org/wiki/Diglyceride  diacylglycerol]'''.<ref name="SPGP"/>. NTSR1 binds to 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>.Recently NTSR1 was crystallized bound with the C-terminus 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 it has a higher potency and efficacy than its full-length counterpart<ref name="SONT"/>. Class A GPCRs bind their ligands within the '''[https://en.wikipedia.org/wiki/Transmembrane_protein transmembrane]''' core in a ligand binding pocket. The <scene name='72/721547/Hydrophobic_binding_pocket/5'>ligand 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'>Na<sup>+</sup> Binding Pocket</scene>. The Na<sup>+</sup> binding pocket is located directly beneath the ligand binding pocket and the two pockets are separated by the residue W321. <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. This has led to a greater understanding of the structure of NTSR1 and how the structure influences its function.
+Neurotensin receptor 1 (NTSR1) is a '''[https://en.wikipedia.org/wiki/G_protein%E2%80%93coupled_receptor G-protein coupled receptor (GPCR).]''' GPCRs are a class of proteins with an extracellular binding domain and 7 transmembrane helices found only in '''[https://en.wikipedia.org/wiki/Eukaryote. eukaryotes]''' that assist in propagating a cellular response. This is accomplished by the binding of molecules to the GPCR outside the cell,causing a '''[https://en.wikipedia.org/wiki/Conformational_change conformational change]''' and activating a '''[https://en.wikipedia.org/wiki/Signal_transduction signal transduction]''' pathway via '''[https://en.wikipedia.org/wiki/Second_messenger_system second messengers]''' such as '''[https://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphate  cyclic AMP]''', '''[https://en.wikipedia.org/wiki/Inositol_trisphosphate  inositol triphosphate]''', and '''[https://en.wikipedia.org/wiki/Diglyceride  diacylglycerol]'''.<ref name="SPGP"/>. NTSR1 binds to 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>.Recently NTSR1 was crystallized bound with the C-terminus 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 it has a higher potency and efficacy than its full-length counterpart<ref name="SONT"/>. Class A GPCRs bind their ligands within the '''[https://en.wikipedia.org/wiki/Transmembrane_protein transmembrane]''' core in a ligand binding pocket. The <scene name='72/721547/Hydrophobic_binding_pocket/5'>ligand 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'>Na<sup>+</sup> Binding Pocket</scene>. The Na<sup>+</sup> binding pocket is located directly beneath the ligand binding pocket and the two pockets are separated by the residue Trp321. <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. This has led to a greater understanding of the structure of NTSR1 and how the structure influences its function.
 == Structure ==
@@ Line 10: / Line 10: @@
 On the extracellular side of the protein is the
 <scene name='72/721547/Hydrophobic_binding_pocket/5'>hydrophobic binding pocket</scene>.
-One key residue in this pocket is a Phenylalanine at position 358, and its purpose is to take part in a network of hydrophobic stacking interactions. These interactions stabilize the Trp321 and Tyr324 residues allowing Tyr324 to interact with the C-terminal
+One key residue in this pocket is a Phenylalanine at position 358, and its purpose is to take part in a network of hydrophobic stacking interactions. These interactions stabilize the Trp321 and Tyr324 residues allowing Tyr324 to interact with the '''[https://en.wikipedia.org/wiki/C-terminus C-terminal]'''
 <scene name='72/721547/Ligand_protein_interactions/7'>Leu13 residue of the NTS ligand</scene>
 via '''[https://en.wikipedia.org/wiki/Van_der_Waals_force Van der Waals interactions]''' .
@@ Line 16: / Line 16: @@
 ===Na<sup>+</sup> Binding Pocket===
-[[Image:Na+ Proteopedia Picture.png |300 px|left|thumb|Figure 2. Residues of collapsed sodium binding pocket. Trp321 (blue) sets the top of the pocket, where Ser362, Asp113, Thr156 and Asn365 (gray) are involved in hydrogen bonding interactions preventing the coordination of a Na+ ion.]]
+[[Image:Na+ Proteopedia Picture.png |300 px|left|thumb|Figure 2. Residues of collapsed sodium binding pocket. Trp321 (blue) sets the top of the pocket, where Ser362, Asp113, Thr156 and Asn365 (gray) are involved in hydrogen bonding interactions preventing the coordination of a Na<sup>+</sup> ion.]]
 <scene name='72/721548/Trp321/1'>Trp321</scene>, which is positioned at the bottom of the <scene name='72/721547/Hydrophobic_binding_pocket/5'>hydrophobic binding pocket</scene>, sets the top of the <scene name='72/721548/Na_bind_pocket/12'> Na<sup>+</sup> Binding Pocket</scene>. The Na<sup>+</sup> ion binding pocket acts as a negative allosteric site for G protein activity <ref name="SPGP"/>. When Na<sup>+</sup> enters the Na<sup>+</sup> ion binding pocket, it coordinates with Asp95, Gln131, Ser135, and Asp113, decreasing the signaling activity of NTSR1 <ref name="SPGP"/>. When NTSR1 is in its active state, the Na<sup>+</sup> ion binding pocket is collapsed, preventing the regulations of protein activity through a Na<sup>+</sup> ion, as the Na<sup>+</sup> ion is unable to be coordinated by a salt bridge to Asp113 (Figure 2). The side chain atoms of Asp113 form a '''[https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bond]''' network with Thr156, Ser361, Ser362, and Gln365 instead, which prevents the coordination of a Na+ ion<ref name ="SPGP"/> (Figure 2).