User:Daniel Schemenauer/Sandbox 1

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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 comprising 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 are Intracellular Loop (ICL) 1 forming a short α-helix, ICL3 and Extracellular Loops (ECL) 1 and 3, which lack secondary structure, and ECL2, which interacts with trans-membrane (TM) helices 1,2 and 3 and 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 comprising 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 are Intracellular Loop (ICL) 1 forming a short α-helix, ICL3 and Extracellular Loops (ECL) 1 and 3, which lack secondary structure, and ECL2, which interacts with trans-membrane (TM) helices 1,2 and 3 and ECL 1<ref name="Primary">PMID: 25042998 </ref>.
===Key Interactions===
===Key Interactions===
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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 is mutated to alanine high levels of activity are seen in the mutant GPCR<ref name="Primary">PMID: 25042998 </ref>.
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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 is mutated to alanine high levels of activity are seen in the mutant GPCR<ref name="Primary">PMID: 25042998 </ref>.
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<scene name='72/726409/Hydrogen_bond_614-668/1'>Hydrogen Bond S614,A668</scene>
 
<scene name='72/726404/Scene_6/3'>Disulfide Bridge C644,C733</scene>
<scene name='72/726404/Scene_6/3'>Disulfide Bridge C644,C733</scene>
<scene name='72/726409/Electrogradient2/3'>ECL2 Binding Cap</scene>
<scene name='72/726409/Electrogradient2/3'>ECL2 Binding Cap</scene>

Revision as of 14:56, 28 March 2016

mGlu5

Drag the structure with the mouse to rotate

References

  1. ↑ Vassilatis DK, Hohmann JG, Zeng H, Li F, Ranchalis JE, Mortrud MT, Brown A, Rodriguez SS, Weller JR, Wright AC, Bergmann JE, Gaitanaris GA. The G protein-coupled receptor repertoires of human and mouse. Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4903-8. Epub 2003 Apr 4. PMID:12679517 doi:http://dx.doi.org/10.1073/pnas.0230374100
  2. ↑ 2.0 2.1 Venkatakrishnan AJ, Deupi X, Lebon G, Tate CG, Schertler GF, Babu MM. Molecular signatures of G-protein-coupled receptors. Nature. 2013 Feb 14;494(7436):185-94. doi: 10.1038/nature11896. PMID:23407534 doi:http://dx.doi.org/10.1038/nature11896
  3. ↑ Pin JP, Galvez T, Prezeau L. Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. Pharmacol Ther. 2003 Jun;98(3):325-54. PMID:12782243
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Dore AS, Okrasa K, Patel JC, Serrano-Vega M, Bennett K, Cooke RM, Errey JC, Jazayeri A, Khan S, Tehan B, Weir M, Wiggin GR, Marshall FH. Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. Nature. 2014 Jul 31;511(7511):557-62. doi: 10.1038/nature13396. Epub 2014 Jul 6. PMID:25042998 doi:http://dx.doi.org/10.1038/nature13396

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Daniel Schemenauer

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