User:Daniel Schemenauer/Sandbox 1: Difference between revisions

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mGlu<sub>5</sub> is seen as a [https://en.wikipedia.org/wiki/Protein_dimer homodimer] ''in vivo,'' with each subunit being comprised of three domains: extracellular, trans-membrane and cysteine-rich.  The structures shown here are centered on the trans-membrane domain, comprised of seven α-helices all roughly parallel to one another<ref name="Primary">PMID: 25042998 </ref>. Also displayed is the Intracellular Loop (ICL) 1 which forms a short α-helix.  Additionally, ICL3 and Extracellular Loops (ECL) 1 and 3 all lack secondary structure, and ECL2 interacts with trans-membrane (TM) helices 1,2, and 3 as well as ECL 1<ref name="Primary">PMID: 25042998 </ref>.
mGlu<sub>5</sub> is seen as a [https://en.wikipedia.org/wiki/Protein_dimer homodimer] ''in vivo,'' with each subunit being comprised of three domains: extracellular, trans-membrane and cysteine-rich.  The structures shown here are centered on the trans-membrane domain, comprised of seven α-helices all roughly parallel to one another<ref name="Primary">PMID: 25042998 </ref>. Also displayed is the Intracellular Loop (ICL) 1 which forms a short α-helix.  Additionally, ICL3 and Extracellular Loops (ECL) 1 and 3 all lack secondary structure, and ECL2 interacts with trans-membrane (TM) helices 1,2, and 3 as well as ECL 1<ref name="Primary">PMID: 25042998 </ref>.
===Key Interactions===
===Key Interactions===
A number of intramolecular interactions within the trans-membrane domain stabilize the inactive conformation of mGlu<sub>5</sub>.  The first of these interactions is an ionic interaction, termed the <scene name='72/726409/Ionic_lock2/1'>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 mutated to 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_614-668/1'>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>.  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 mutated to 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_614-668/1'>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 ECL2 is critical at anchoring ECL2 and is highly conserved across Class C GPCR’s<ref name="Primary">PMID: 25042998 </ref>.  The ECL2 position combined with the helical bundle of the trans-membrane domain creates a <scene name='72/726409/Electrogradient2/3'>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>.
A <scene name='72/726404/Scene_6/8'>Disulfide Bond </scene> between Cysteine 644 of TM3 and Cysteine 733 of ECL2 is critical at anchoring ECL2 and is highly conserved across Class C GPCR’s<ref name="Primary">PMID: 25042998 </ref>.  The ECL2 position combined with the helical bundle of the trans-membrane domain creates a <scene name='72/726409/Electrogradient2/3'>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>.
===Comparison with Class A and B GPCRs===
===Comparison with Class A and B GPCRs===
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