User:Daniel Schemenauer/Sandbox 1: Difference between revisions
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===Interactions with a Negative Allosteric Modulator=== | ===Interactions with a Negative Allosteric Modulator=== | ||
The structure of mGlu<sub>5</sub> bound to the NAM [https://en.wikipedia.org/wiki/Mavoglurant Mavoglurant] demonstrates how protein activity is decreased through drug interactions. | The structure of mGlu<sub>5</sub> bound to the NAM [https://en.wikipedia.org/wiki/Mavoglurant Mavoglurant] demonstrates how protein activity is decreased through drug interactions. | ||
<scene name='72/726404/Scene_7/ | <scene name='72/726404/Scene_7/5'>Mavoglurant</scene> binds within the allosteric binding site in the core of the seven trans-membrane α-helices, having passed through the restricted entrance formed by the <scene name='72/726409/Mavoglurant_overview2/3'>ECL2</scene>. Bound Mavoglurant forms multiple interactions with the protein that further stabilize the inactive conformation. | ||
The bicyclic ring system of the drug is surrounded by a pocket of mainly hydrophobic residues including Val 806, Met 802, Phe 788, Trp 785, Leu 744, Ile 651, Pro 655, and Asn 747<ref name="Primary">PMID: 25042998 </ref> (Figure 1). The carbamate tail of Mavoglurant forms a hydrogen bond through its carbonyl oxygen to the amide side-chain of Asparagine 747 of TM4 (Figure 2). A hydroxyl group similarly forms hydrogen bonds to mGlu<sub>5</sub>, specifically at two serine residues (S805 and S809) of TM7. These residues form a hydrogen bonding network to other residues through their main chain atoms and a coordinated water molecule (omitted for clarity) (Figure 3). The interactions between Mavoglurant and mGlu<sub>5</sub> involve TM helices that were not previously stabilized by any strong interactions, introducing a new level of stability that favors the inactive conformation of the protein and hence decreases the overall activity of mGlu<sub>5</sub><ref name="Primary">PMID: 25042998 </ref>. | The bicyclic ring system of the drug is surrounded by a pocket of mainly hydrophobic residues including Val 806, Met 802, Phe 788, Trp 785, Leu 744, Ile 651, Pro 655, and Asn 747<ref name="Primary">PMID: 25042998 </ref> (Figure 1). The carbamate tail of Mavoglurant forms a hydrogen bond through its carbonyl oxygen to the amide side-chain of Asparagine 747 of TM4 (Figure 2). A hydroxyl group similarly forms hydrogen bonds to mGlu<sub>5</sub>, specifically at two serine residues (S805 and S809) of TM7. These residues form a hydrogen bonding network to other residues through their main chain atoms and a coordinated water molecule (omitted for clarity) (Figure 3). The interactions between Mavoglurant and mGlu<sub>5</sub> involve TM helices that were not previously stabilized by any strong interactions, introducing a new level of stability that favors the inactive conformation of the protein and hence decreases the overall activity of mGlu<sub>5</sub><ref name="Primary">PMID: 25042998 </ref>. | ||
[[Image:Mav_Hydrophobic_pocket.png |300 px|left|thumb|Figure 1. Hydrophobic Pocket Surrounding Mavoglurant]] | [[Image:Mav_Hydrophobic_pocket.png |300 px|left|thumb|Figure 1. Hydrophobic Pocket Surrounding Mavoglurant]] | ||
