User:Daniel Schemenauer/Sandbox 1: Difference between revisions
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===Key Interactions=== | ===Key Interactions=== | ||
A number of intramolecular interactions within the trans-membrane domain stabilize the inactive conformation of mGlu<sub>5</sub>, and demonstrated by <scene name='72/726409/Overview/5'>mGlu<sub>5</sub></scene> being represented in the inactivate state, the capacity for glutamate to bind to the mGlu<sub>5</sub> receptor is critically hindered, thus decreasing the aforementioned [https://en.wikipedia.org/wiki/Gq_alpha_subunit G<sub>q</sub> pathway]. The first of these interactions is an ionic interaction, termed the <scene name='72/726409/Ionic_lock2/2'>Ionic Lock</scene>, between Lysine 665 of TM3 and Glutamate 770 of TM6. Evidence for the importance of this interaction came through a kinetic study of mutant proteins where both residues were separately substituted with alanine, resulting in constitutive activity of the GPCR and its coupled pathway<ref name="Primary">PMID: 25042998 </ref>. A second critical interaction that stabilizes the inactive conformer is a <scene name='72/726409/Hydrogen_bond_614-668/2'>Hydrogen Bond </scene> between Serine 614 of ICL1 and Arginine 668 of TM3. Similarly, when Serine 614 was mutated to alanine, high levels of activity were seen in the mutant GPCR<ref name="Primary">PMID: 25042998 </ref>. | A number of intramolecular interactions within the trans-membrane domain stabilize the inactive conformation of mGlu<sub>5</sub>, and demonstrated by <scene name='72/726409/Overview/5'>mGlu<sub>5</sub></scene> being represented in the inactivate state, the capacity for glutamate to bind to the mGlu<sub>5</sub> receptor is critically hindered, thus decreasing the aforementioned [https://en.wikipedia.org/wiki/Gq_alpha_subunit G<sub>q</sub> pathway]. The first of these interactions is an ionic interaction, termed the <scene name='72/726409/Ionic_lock2/2'>Ionic Lock</scene>, between Lysine 665 of TM3 and Glutamate 770 of TM6. Evidence for the importance of this interaction came through a kinetic study of mutant proteins where both residues were separately substituted with alanine, resulting in constitutive activity of the GPCR and its coupled pathway<ref name="Primary">PMID: 25042998 </ref>. A second critical interaction that stabilizes the inactive conformer is a <scene name='72/726409/Hydrogen_bond_614-668/2'>Hydrogen Bond </scene> between Serine 614 of ICL1 and Arginine 668 of TM3. Similarly, when Serine 614 was mutated to alanine, high levels of activity were seen in the mutant GPCR<ref name="Primary">PMID: 25042998 </ref>. | ||
A <scene name='72/726404/Scene_6/8'>Disulfide Bond </scene> between Cysteine 644 of TM3 and Cysteine 733 of <scene name='72/726409/Mavoglurant_overview2/3'>ECL2</scene> is critical at anchoring ECL2 and is highly conserved across Class C GPCR’s<ref name="Primary">PMID: 25042998 </ref>. The ECL2's presence combined with the helical bundle of the trans-membrane domain creates a <scene name='72/726409/Electrogradient2/ | A <scene name='72/726404/Scene_6/8'>Disulfide Bond </scene> between Cysteine 644 of TM3 and Cysteine 733 of <scene name='72/726409/Mavoglurant_overview2/3'>ECL2</scene> is critical at anchoring ECL2 and is highly conserved across Class C GPCR’s<ref name="Primary">PMID: 25042998 </ref>. The ECL2's presence combined with the helical bundle of the trans-membrane domain creates a <scene name='72/726409/Electrogradient2/9'>Binding Cap</scene> that restricts entrance to the allosteric binding site within the seven trans-membrane α-helices. This restricted entrance has no effect on the natural ligand, glutamate, as it binds to the extracellular domain, but this entrance dictates potential drug targets that act through allosteric modulation<ref name="Primary">PMID: 25042998 </ref>. | ||
== Clinical Relevance == | == Clinical Relevance == | ||
