Sandbox Reserved 1160
From Proteopedia
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Receiving and responding to extracellular messages is critical to the proper function of the nervous system. Glutamate is the primary excitory neurotransmitter of the Central Nervous System (CNS), and metabotropic glutamate receptor 5 is a key member of the glutamate signaling pathway<ref name="Dore" />. Metabotropic glutamate receptor 5 is a homodimeric [[GPCR]] that resides in the cellular membrane <ref name="Dore" />. mGlu5 is a member of the Class C GPCR family and can further be categorized into the Group I subgroup<ref name="Wu" />. | Receiving and responding to extracellular messages is critical to the proper function of the nervous system. Glutamate is the primary excitory neurotransmitter of the Central Nervous System (CNS), and metabotropic glutamate receptor 5 is a key member of the glutamate signaling pathway<ref name="Dore" />. Metabotropic glutamate receptor 5 is a homodimeric [[GPCR]] that resides in the cellular membrane <ref name="Dore" />. mGlu5 is a member of the Class C GPCR family and can further be categorized into the Group I subgroup<ref name="Wu" />. | ||
The functionality of the mGlu5 receptor is determined by conformational changes throughout multiple domains. mGlu5 will bind glutamate through its 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 the activation of [[PKC]]<ref name="Wu" />. The signal is relayed through a Gq/11 pathway<ref name="Dore" />. Activated PKC will elicit a excitory post-synaptic response and modulate long term potentiation<ref name="Wu" />. | The functionality of the mGlu5 receptor is determined by conformational changes throughout multiple domains. mGlu5 will bind glutamate through its 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 the activation of [[PKC]]<ref name="Wu" />. The signal is relayed through a Gq/11 pathway<ref name="Dore" />. Activated PKC will elicit a excitory post-synaptic response and modulate long term potentiation<ref name="Wu" />. | ||
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Human mGlu5 is found throughout the central nervous system. Areas containing high concentrations of mGlu5 are often involved in emotional processing and higher cognition<ref name="Niswender" />. The localization of mGlu5 in the CNS and the presence of multiple domains makes mGlu5 an excellent target for treating neurological conditions including: schizophrenia,[http://www.fragilex.org/fragile-x/fragile-x-syndrome/ Fragile X], depression, anxiety, and Alzheimer's disease<ref name="Wu" />. | Human mGlu5 is found throughout the central nervous system. Areas containing high concentrations of mGlu5 are often involved in emotional processing and higher cognition<ref name="Niswender" />. The localization of mGlu5 in the CNS and the presence of multiple domains makes mGlu5 an excellent target for treating neurological conditions including: schizophrenia,[http://www.fragilex.org/fragile-x/fragile-x-syndrome/ Fragile X], depression, anxiety, and Alzheimer's disease<ref name="Wu" />. | ||
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The mGlu family of receptors was the first of the Class C [[GPCR]] to be extensively studied<ref name="Wu" />. The first regions of the protein crystallized and studied were the Venus Fly Trap domain and the cystiene -rich domain on the extracellular region of the receptor<ref name="Dore" />.The Venus Flytrap domain is a large extracellular domain that will selectively bind to glutamate<ref name="Wu" />. The CRD is a somewhat smaller domain composed of many B sheets and cystiene residues <ref name="Wu" />. The CRD acts as a signal mediator between the Venus Flytrap domain and the TMD of mGlu5, by linking to each domain with disulfide bonds<ref name="Wu" />. The hydrophobic nature and flexibility of the transmembrane domain made it difficult to crystallize. Recently, the human metabotropic glutamate receptor 5 transmembrane domain (TMD) was crystallized and a structure elucidated<ref name="Dore" />. Several modifications made to the TMD for successful crystallization. The protein was thermostabilized and flexible domains were removed<ref name="Dore" />. In total residue 2-568 and residues 837-1153 were excised from the structure. Also, a T4 -<scene name='72/721531/Protien_lys/1'>Lysozyme</scene> was inserted into ICL-2 to add stability<ref name="Dore" />. | The mGlu family of receptors was the first of the Class C [[GPCR]] to be extensively studied<ref name="Wu" />. The first regions of the protein crystallized and studied were the Venus Fly Trap domain and the cystiene -rich domain on the extracellular region of the receptor<ref name="Dore" />.The Venus Flytrap domain is a large extracellular domain that will selectively bind to glutamate<ref name="Wu" />. The CRD is a somewhat smaller domain composed of many B sheets and cystiene residues <ref name="Wu" />. The CRD acts as a signal mediator between the Venus Flytrap domain and the TMD of mGlu5, by linking to each domain with disulfide bonds<ref name="Wu" />. The hydrophobic nature and flexibility of the transmembrane domain made it difficult to crystallize. Recently, the human metabotropic glutamate receptor 5 transmembrane domain (TMD) was crystallized and a structure elucidated<ref name="Dore" />. Several modifications made to the TMD for successful crystallization. The protein was thermostabilized and flexible domains were removed<ref name="Dore" />. In total residue 2-568 and residues 837-1153 were excised from the structure. Also, a T4 -<scene name='72/721531/Protien_lys/1'>Lysozyme</scene> was inserted into ICL-2 to add stability<ref name="Dore" />. | ||
== Structure== | == Structure== | ||
| - | [[Image:STR.png|200 px|left|thumb|Figure 1: Overall Structure of the mGlu5 TMD. The polar heads on the Oliec acids orient the image with the top oriented extracellularly, the middle portion inserted into the membrane, and the lower portion oriented intracellularly. ]] | + | [[Image:STR.png|200 px|left|thumb|'''Figure 1''': Overall Structure of the mGlu5 TMD. The polar heads on the Oliec acids orient the image with the top oriented extracellularly, the middle portion inserted into the membrane, and the lower portion oriented intracellularly. The white exterior represents the surface of the protien, and the multicolored lones interior to the surface represent the backbones 7 transmembrane alpha helices. ]] |
=== Overview === | === Overview === | ||
The mGlu5 TMD contains 7 <scene name='72/721531/Protien_7_helices/2'> alpha helices</scene> that spans the membrane. The protein was crystallized with Oleic acid and MES. On the superior portion of the protein there are several critical extracellular loops. The binding pocket can be found near the middle of the protein. Inserted into the biding pocket is the negative allosteric modulator [http://www.en.wikipedia.org/wiki/Mavoglurant mavoglurant]. It is important to note that the TMD as illustrated is in an inactive conformation. On the intracellular portion of the protein there exist several ionic locks whose positions will determine the activity of the protein. | The mGlu5 TMD contains 7 <scene name='72/721531/Protien_7_helices/2'> alpha helices</scene> that spans the membrane. The protein was crystallized with Oleic acid and MES. On the superior portion of the protein there are several critical extracellular loops. The binding pocket can be found near the middle of the protein. Inserted into the biding pocket is the negative allosteric modulator [http://www.en.wikipedia.org/wiki/Mavoglurant mavoglurant]. It is important to note that the TMD as illustrated is in an inactive conformation. On the intracellular portion of the protein there exist several ionic locks whose positions will determine the activity of the protein. | ||
Revision as of 23:06, 7 April 2016
Human metabotropic glutamate receptor 5 transmembrane domain
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