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From Proteopedia
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== Human metabotropic glutamate receptor 5 transmembrane domain == | == Human metabotropic glutamate receptor 5 transmembrane domain == | ||
<StructureSection load='4oo9' size='300' frame='true' side='right' caption='Human metabotropic glutamate receptor 5 transmembrane domain' scene='72/721531/Protien_clean_sce/1'> | <StructureSection load='4oo9' size='300' frame='true' side='right' caption='Human metabotropic glutamate receptor 5 transmembrane domain' scene='72/721531/Protien_clean_sce/1'> | ||
| - | Receiving and responding to extracellular messages is critical to the proper function of the nervous system. Glutamate is the major excitory neurotransmitter of the CNS, and metabotropic glutamate receptor 5 will play a major role in glutamate signaling. Metabotropic glutamate receptor 5 transmembrane domain is a homodimeric [[GPCR]] that resides in the cellular membrane <ref name="Dore" />. This domain is a member of the Class C GPCR family and can further be categorized into the Group I subgroup. The transmembrane domain will signal through a Gq/11 pathway. mGlu5 will bind glutamate to the extracellular Venus flytrap domain and the signal will be transduced across the membrane to a heterotrimeric G protein, which will ultimately lead to calcium release and activation of PKC. This will elicit a excitory post-synaptic repose and modulate long term potentiation. Human metabotropic glutamate receptor 5 is found throughout the central nervous system. Areas containing high concentrations of this protein are often involved involved in emotions and higher cognition<ref name="Niswender" />. The localization of mGlu5 in the CNS and the presence of multiple domains makes mGlu5 a possible target for treating schizophrenia,[http://www.fragilex.org/fragile-x/fragile-x-syndrome/ Fragile X], depression, anxiety,and Alzheimer's disease<ref name="Wu" />. | + | Receiving and responding to extracellular messages is critical to the proper function of the nervous system. Glutamate is the major excitory neurotransmitter of the CNS, and metabotropic glutamate receptor 5 will play a major role in glutamate signaling. Metabotropic glutamate receptor 5 transmembrane domain is a homodimeric [[GPCR]] that resides in the cellular membrane <ref name="Dore" />. This domain is a member of the Class C GPCR family and can further be categorized into the Group I subgroup<ref name="Wu" />. The transmembrane domain will signal through a Gq/11 pathway<ref name="Dore" />. mGlu5 will bind glutamate to the extracellular Venus flytrap domain and the signal will be transduced across the membrane to a heterotrimeric G protein, which will ultimately lead to calcium release and activation of PKC<ref name="Wu" />. This will elicit a excitory post-synaptic repose and modulate long term potentiation<ref name="Wu" />. Human metabotropic glutamate receptor 5 is found throughout the central nervous system. Areas containing high concentrations of this protein are often involved involved in emotions and higher cognition<ref name="Niswender" />. The localization of mGlu5 in the CNS and the presence of multiple domains makes mGlu5 a possible target for treating schizophrenia,[http://www.fragilex.org/fragile-x/fragile-x-syndrome/ Fragile X], depression, anxiety,and Alzheimer's disease<ref name="Wu" />. |
== Discovery == | == Discovery == | ||
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=== Extracellular Domain === | === Extracellular Domain === | ||
=== Binding Pocket === | === Binding Pocket === | ||
| - | The binding pocket represents an interesting source of regulatory control of receptor activity. The binding pocket is only accessible by a relatively narrow (7 angstrom) <scene name='72/721531/Protien_sur/4'>entrance</scene>. This small entrance severely restricts the access of both positive and negative allosteric regulators. This structural feature will severely limit the size of possible regulators. | + | The binding pocket represents an interesting source of regulatory control of receptor activity. The binding pocket is only accessible by a relatively narrow (7 angstrom) <scene name='72/721531/Protien_sur/4'>entrance</scene><ref name="Dore" />. This small entrance severely restricts the access of both positive and negative allosteric regulators. This structural feature will severely limit the size of possible regulators. |
| - | Important Amino Acids: | + | Important Amino Acids<ref name="Dore" />: |
| - | *<scene name='72/721531/Protien_bindtop/4'>Asparagine</scene> 747forms a hydrogen bond network with main chain carbonyl of | + | *<scene name='72/721531/Protien_bindtop/4'>Asparagine</scene> 747forms a hydrogen bond network with the main chain carbonyl of Glycine 652 and the carbamate portion of mavoglurant. |
*Bicyclic ring surrounded by <scene name='72/721531/Protien_hydrophobic/1'>hydrophobic binding pocket</scene>. | *Bicyclic ring surrounded by <scene name='72/721531/Protien_hydrophobic/1'>hydrophobic binding pocket</scene>. | ||
*2 Catalytic <scene name='72/721531/Protien_bindmiddle/2'>serine</scene> resides H-bond to the hyrdoxyl oxygen of our ligand. | *2 Catalytic <scene name='72/721531/Protien_bindmiddle/2'>serine</scene> resides H-bond to the hyrdoxyl oxygen of our ligand. | ||
*A <scene name='72/721531/Protien_bindbottom/1'>water molecular</scene> inside of the binding pocket helps stabilize the inactive state. | *A <scene name='72/721531/Protien_bindbottom/1'>water molecular</scene> inside of the binding pocket helps stabilize the inactive state. | ||
| - | Once bound to mavoglurant, transmembrane helix 7 undergoes a conformational change. The shifting of TM7 will lead to a more global conformational change, which we leave the receptor incapable of signaling. | + | Once bound to mavoglurant, transmembrane helix 7 undergoes a conformational change<ref name="Dore" />. The shifting of TM7 will lead to a more global conformational change, which we leave the receptor incapable of signaling<ref name="Dore" />. |
=== Ionic Locks === | === Ionic Locks === | ||
| - | Another important structural feature of the protein is the series of <scene name='72/721531/Ionic_lock/2'>ionic locks</scene> on the intracellular side of the protein. Interaction between amino acids will form a salt bridge which will stabilize the inactive conformation. The primary ionic lock forms between Glu770, Lys665, and Ser613. A secondary ionic lock occurs between Ser614 and Arg668. The purpose of these ionic locks | + | Another important structural feature of the protein is the series of <scene name='72/721531/Ionic_lock/2'>ionic locks</scene> on the intracellular side of the protein. Interaction between amino acids will form a salt bridge which will stabilize the inactive conformation<ref name="Dore" />. The primary ionic lock forms between Glu770, Lys665, and Ser613<ref name="Dore" />. A secondary ionic lock occurs between Ser614 and Arg668<ref name="Dore" />. The purpose of these ionic locks is analogous to the ionic interactions that stabilize the T state in [[Hemoglobin]]. In the case of the TMD, when the NAM mavoglurant is bound the ionic lock is formed. This stabilizes the inactive state, where the intracellular loops are stabilized inwards<ref name="Wu" />. This will effectively block the crevice that is involved in binding the G-protein<ref name="Wu" />. Models have suggested that, even in a glutamate bound state, the mavoglurant bound receptor would be dimerized but incapable of signaling<ref name="Wu" />. This helps maintain the readiness of the pathway, while still decreasing signal response. |
== Function and Pathway == | == Function and Pathway == | ||
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=== Parkinsons === | === Parkinsons === | ||
| - | == Structural highlights == | ||
| - | <scene name='72/721531/Protien_sur/1'>TextToBeDisplayed</scene> | ||
| - | <scene name='72/721531/Protien_sur | ||
| - | <scene name='72/721531/Protien_7_helices/1'>7 Helices</scene> | ||
| - | This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes. | ||
| - | <scene name='72/721531/Protien_sur/3'>TextToBeDisplayed</scene> | ||
| - | </StructureSection> | ||
== References == | == References == | ||
<ref name="Dore">PMID: 25042998</ref> | <ref name="Dore">PMID: 25042998</ref> | ||
Revision as of 02:51, 30 March 2016
Human metabotropic glutamate receptor 5 transmembrane domain
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