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>. 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_lock2/1'>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 <scene name='72/726404/Scene_6/ | A <scene name='72/726404/Scene_6/5'>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=== | ||
The structure of the trans-membrane domain of mGlu<sub>5</sub> was compared to rhodopsin, a class A GPCR, and CRF<sub>1</sub>R, a class B GPCR. The superimposition of all three structures demonstrated the greatest divergence occurred across the top half of the trans-membrane bundle, attributing to the different extracellular domains that accompany each GPCR class. Furthermore, mGlu<sub>5</sub> TM7 is shifted inwards 5 Å compared to the class A GPCR, and TM5 is shifted inwards 6 Å compared to both GPCRs, thus narrowing the allosteric binding entrance<ref name="Primary">PMID: 25042998 </ref>. | The structure of the trans-membrane domain of mGlu<sub>5</sub> was compared to rhodopsin, a class A GPCR, and CRF<sub>1</sub>R, a class B GPCR. The superimposition of all three structures demonstrated the greatest divergence occurred across the top half of the trans-membrane bundle, attributing to the different extracellular domains that accompany each GPCR class. Furthermore, mGlu<sub>5</sub> TM7 is shifted inwards 5 Å compared to the class A GPCR, and TM5 is shifted inwards 6 Å compared to both GPCRs, thus narrowing the allosteric binding entrance<ref name="Primary">PMID: 25042998 </ref>. | ||
