Sandbox Reserved 1165: Difference between revisions

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=Structures of Class A vs. Class B GPCRs=

Comparison of the <scene name='72/721536/7tm/2'>Class B GCGR 7TM</scene> was compared to that of a <scene name='72/721536/Class_a/1'>class A 7TM</scene>, and it was found that the orientation and positioning of the [https://en.wikipedia.org/wiki/Alpha_helix alpha helices] are conserved through both classes. But, structural alignments of the two revealed multiple gaps in the transmembrane region signifying a variety of structural deviations in transmembrane helices <ref name="Tips">PMID: 23863937</ref>. The N-terminal end of helix one in class B GCGR, located in the 7TM, is longer than any known class A GPCR structure and stretches three supplementary helical turns above the extracellular (EC) membrane boundary. This region is referred to as the stalk and is involved in glucagon binding and helps in defining the orientation of the ECD with respect to the 7TM domain <ref name="Tips">PMID: 23863937</ref>. Also specific to class B GPCRs, a [https://en.wikipedia.org/wiki/Glycine glycine] (Gly) residue at position 393 induces a <scene name='72/721535/Helical_bend/2'>bend in helix VII</scene>; this bend is stabilized by the [http://chemwiki.ucdavis.edu/Core/Physical_Chemistry/Physical_Properties_of_Matter/Atomic_and_Molecular_Properties/Intermolecular_Forces/Hydrophobic_Interactions hydrophobic interaction] between the <scene name='72/721535/Gly_393_phe_184/1'>glycine 393 and phenylalanine 184</scene>. One of the most distinguishable characteristics of the class B 7TM is the helix VIII tilt of 25 degrees compared to that of class A, which has no tilt. This results from a [https://en.wikipedia.org/wiki/Phenylalanine glutamate] Glu) 406 in helix VIII that is fully conserved in secretin-like receptors and forms two interhelical [https://en.wikipedia.org/wiki/Salt_bridge_(protein_and_supramolecular) salt bridges] with [https://simple.wikipedia.org/wiki/Conserved_sequence conserved residues] [https://en.wikipedia.org/wiki/Arginine arginine] (Arg) 173 and arginine 346 <ref name="Tips">PMID: 23863937</ref>. Despite these differences, a vital region that is conserved in both class B and class A receptors is the [https://en.wikipedia.org/wiki/Disulfide disulphide bond] between [https://en.wikipedia.org/wiki/Cysteine cysteine] <scene name='72/721535/Disulfide_bond_notspin/1'>(Cys) 294 and cysteine 224</scene> in extracellular loop two (ECL2). This bond stabilizes the receptors entire 7TM fold. Lastly, the locations of the extracellular tips for class B glucagon receptors allow for a much wider and deeper binding cavity in the [https://en.wikipedia.org/wiki/Ligand_(biochemistry) ligand-binding pocket], which is much more immense than any of the class A GCGRs <ref name="Tips">PMID: 23863937</ref>. These wide ranges specifically occur between two sets of alpha helices, as seen in '''Figure 2''' below.

Comparison of the <scene name='72/721536/7tm/2'>Class B GCGR 7TM</scene> was compared to that of a <scene name='72/721536/Class_a/1'>class A 7TM</scene>, and it was found that the orientation and positioning of the [https://en.wikipedia.org/wiki/Alpha_helix alpha helices] are conserved through both classes. But, structural alignments of the two revealed multiple gaps in the transmembrane region signifying a variety of structural deviations in transmembrane helices <ref name="Tips">PMID: 23863937</ref>. The N-terminal end of helix one in class B GCGR, located in the 7TM, is longer than any known class A GPCR structure and stretches three supplementary helical turns above the extracellular (EC) membrane boundary. This region is referred to as the <scene name='72/721535/Opening_orientation/2'>stalk</scene> and is involved in glucagon binding and helps in defining the orientation of the ECD with respect to the 7TM domain <ref name="Tips">PMID: 23863937</ref>. Also specific to class B GPCRs, a [https://en.wikipedia.org/wiki/Glycine glycine] (Gly) residue at position 393 induces a <scene name='72/721535/Helical_bend/2'>bend in helix VII</scene>; this bend is stabilized by the [http://chemwiki.ucdavis.edu/Core/Physical_Chemistry/Physical_Properties_of_Matter/Atomic_and_Molecular_Properties/Intermolecular_Forces/Hydrophobic_Interactions hydrophobic interaction] between the <scene name='72/721535/Gly_393_phe_184/1'>glycine 393 and phenylalanine 184</scene>. One of the most distinguishable characteristics of the class B 7TM is the helix VIII tilt of 25 degrees compared to that of class A, which has no tilt. This results from a [https://en.wikipedia.org/wiki/Phenylalanine glutamate] Glu) 406 in helix VIII that is fully conserved in secretin-like receptors and forms two interhelical [https://en.wikipedia.org/wiki/Salt_bridge_(protein_and_supramolecular) salt bridges] with [https://simple.wikipedia.org/wiki/Conserved_sequence conserved residues] [https://en.wikipedia.org/wiki/Arginine arginine] (Arg) 173 and arginine 346 <ref name="Tips">PMID: 23863937</ref>. Despite these differences, a vital region that is conserved in both class B and class A receptors is the [https://en.wikipedia.org/wiki/Disulfide disulphide bond] between [https://en.wikipedia.org/wiki/Cysteine cysteine] <scene name='72/721535/Disulfide_bond_notspin/1'>(Cys) 294 and cysteine 224</scene> in extracellular loop two (ECL2). This bond stabilizes the receptors entire 7TM fold. Lastly, the locations of the extracellular tips for class B glucagon receptors allow for a much wider and deeper binding cavity in the [https://en.wikipedia.org/wiki/Ligand_(biochemistry) ligand-binding pocket], which is much more immense than any of the class A GCGRs <ref name="Tips">PMID: 23863937</ref>. These wide ranges specifically occur between two sets of alpha helices, as seen in '''Figure 2''' below.

Line 25:

Many of the [https://en.wikipedia.org/wiki/Residue_(chemistry) residues] that are in direct contact with the glucagon molecule are [https://en.wikipedia.org/wiki/Ion charged] or are [https://en.wikipedia.org/wiki/Chemical_polarity polar].

[[Image:Screen Shot 2016-03-29 at 3.24.43 PM.png|(|):|400 px|right|thumb|'''Figure 4: Salt Bridge'''. The salt bridge is located on the intracellular side at the bottom of the protein, in relation to the orientation it holds within the cell membrane. It is made between residues Glu 406, Arg 173, and Arg 346, as labeled in the figure.]]

There are also many smaller residues on glucagon that support the bulky residues on the GCGR. These residues are located within the <scene name='72/721535/Binding_pocket_orange/1'>binding pocket</scene> of the 7TM <ref name="Ligands">PMID: 21542831</ref>. There are specific amino acid interactions that hold the helices of the 7TM in the closed conformation that maximizes [http://www.chemicool.com/definition/affinity.html affinity]. This includes a [https://en.wikipedia.org/wiki/Disulfide disulfide bond] between <scene name='72/721535/Disulfide_bond_notspin/1'>Cys 294 and Cys 224</scene> mentioned earlier that serves to hold the ECL1 and ECL2 in the proper orientation. Additionally, the [https://en.wikipedia.org/wiki/Salt_bridge_%28protein_and_supramolecular%29 salt bridges] between Glu 406, Arg 173, and Arg 346, also mentioned earlier, hold the conformation together for higher affinity. Finally, alpha helical structure of the ~~<scene name='72/721535/Opening_orientation/2'>~~stalk~~</scene>~~ is imperative to the affinity and binding of the glucagon <ref name="Tips">PMID: 23863937</ref>.

There are also many smaller residues on glucagon that support the bulky residues on the GCGR. These residues are located within the <scene name='72/721535/Binding_pocket_orange/1'>binding pocket</scene> of the 7TM <ref name="Ligands">PMID: 21542831</ref>. There are specific amino acid interactions that hold the helices of the 7TM in the closed conformation that maximizes [http://www.chemicool.com/definition/affinity.html affinity]. This includes a [https://en.wikipedia.org/wiki/Disulfide disulfide bond] between <scene name='72/721535/Disulfide_bond_notspin/1'>Cys 294 and Cys 224</scene> mentioned earlier that serves to hold the ECL1 and ECL2 in the proper orientation. Additionally, the [https://en.wikipedia.org/wiki/Salt_bridge_%28protein_and_supramolecular%29 salt bridges] between Glu 406, Arg 173, and Arg 346, also mentioned earlier, hold the conformation together for higher affinity. Finally, alpha helical structure of the stalk is imperative to the affinity and binding of the glucagon <ref name="Tips">PMID: 23863937</ref>.

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@@ Line 8: / Line 8: @@
 =Structures of Class A vs. Class B GPCRs=
-Comparison of the <scene name='72/721536/7tm/2'>Class B GCGR 7TM</scene> was compared to that of a <scene name='72/721536/Class_a/1'>class A 7TM</scene>, and it was found that the orientation and positioning of the [https://en.wikipedia.org/wiki/Alpha_helix alpha helices] are conserved through both classes. But, structural alignments of the two revealed multiple gaps in the transmembrane region signifying a variety of structural deviations in transmembrane helices <ref name="Tips">PMID: 23863937</ref>. The N-terminal end of helix one in class B GCGR, located in the 7TM, is longer than any known class A GPCR structure and stretches three supplementary helical turns above the extracellular (EC) membrane boundary. This region is referred to as the stalk and is involved in glucagon binding and helps in defining the orientation of the ECD with respect to the 7TM domain <ref name="Tips">PMID: 23863937</ref>. Also specific to class B GPCRs, a [https://en.wikipedia.org/wiki/Glycine glycine] (Gly) residue at position 393 induces a <scene name='72/721535/Helical_bend/2'>bend in helix VII</scene>; this bend is stabilized by the [http://chemwiki.ucdavis.edu/Core/Physical_Chemistry/Physical_Properties_of_Matter/Atomic_and_Molecular_Properties/Intermolecular_Forces/Hydrophobic_Interactions hydrophobic interaction] between the <scene name='72/721535/Gly_393_phe_184/1'>glycine 393 and phenylalanine 184</scene>. One of the most distinguishable characteristics of the class B 7TM is the helix VIII tilt of 25 degrees compared to that of class A, which has no tilt. This results from a [https://en.wikipedia.org/wiki/Phenylalanine glutamate] Glu) 406 in helix VIII that is fully conserved in secretin-like receptors and forms two interhelical [https://en.wikipedia.org/wiki/Salt_bridge_(protein_and_supramolecular) salt bridges] with [https://simple.wikipedia.org/wiki/Conserved_sequence conserved residues] [https://en.wikipedia.org/wiki/Arginine arginine] (Arg) 173 and arginine 346 <ref name="Tips">PMID: 23863937</ref>. Despite these differences, a vital region that is conserved in both class B and class A receptors is the [https://en.wikipedia.org/wiki/Disulfide disulphide bond] between [https://en.wikipedia.org/wiki/Cysteine cysteine] <scene name='72/721535/Disulfide_bond_notspin/1'>(Cys) 294 and cysteine 224</scene> in extracellular loop two (ECL2). This bond stabilizes the receptors entire 7TM fold. Lastly, the locations of the extracellular tips for class B glucagon receptors allow for a much wider and deeper binding cavity in the [https://en.wikipedia.org/wiki/Ligand_(biochemistry) ligand-binding pocket], which is much more immense than any of the class A GCGRs <ref name="Tips">PMID: 23863937</ref>. These wide ranges specifically occur between two sets of alpha helices, as seen in '''Figure 2''' below.
+Comparison of the <scene name='72/721536/7tm/2'>Class B GCGR 7TM</scene> was compared to that of a <scene name='72/721536/Class_a/1'>class A 7TM</scene>, and it was found that the orientation and positioning of the [https://en.wikipedia.org/wiki/Alpha_helix alpha helices] are conserved through both classes. But, structural alignments of the two revealed multiple gaps in the transmembrane region signifying a variety of structural deviations in transmembrane helices <ref name="Tips">PMID: 23863937</ref>. The N-terminal end of helix one in class B GCGR, located in the 7TM, is longer than any known class A GPCR structure and stretches three supplementary helical turns above the extracellular (EC) membrane boundary. This region is referred to as the <scene name='72/721535/Opening_orientation/2'>stalk</scene> and is involved in glucagon binding and helps in defining the orientation of the ECD with respect to the 7TM domain <ref name="Tips">PMID: 23863937</ref>. Also specific to class B GPCRs, a [https://en.wikipedia.org/wiki/Glycine glycine] (Gly) residue at position 393 induces a <scene name='72/721535/Helical_bend/2'>bend in helix VII</scene>; this bend is stabilized by the [http://chemwiki.ucdavis.edu/Core/Physical_Chemistry/Physical_Properties_of_Matter/Atomic_and_Molecular_Properties/Intermolecular_Forces/Hydrophobic_Interactions hydrophobic interaction] between the <scene name='72/721535/Gly_393_phe_184/1'>glycine 393 and phenylalanine 184</scene>. One of the most distinguishable characteristics of the class B 7TM is the helix VIII tilt of 25 degrees compared to that of class A, which has no tilt. This results from a [https://en.wikipedia.org/wiki/Phenylalanine glutamate] Glu) 406 in helix VIII that is fully conserved in secretin-like receptors and forms two interhelical [https://en.wikipedia.org/wiki/Salt_bridge_(protein_and_supramolecular) salt bridges] with [https://simple.wikipedia.org/wiki/Conserved_sequence conserved residues] [https://en.wikipedia.org/wiki/Arginine arginine] (Arg) 173 and arginine 346 <ref name="Tips">PMID: 23863937</ref>. Despite these differences, a vital region that is conserved in both class B and class A receptors is the [https://en.wikipedia.org/wiki/Disulfide disulphide bond] between [https://en.wikipedia.org/wiki/Cysteine cysteine] <scene name='72/721535/Disulfide_bond_notspin/1'>(Cys) 294 and cysteine 224</scene> in extracellular loop two (ECL2). This bond stabilizes the receptors entire 7TM fold. Lastly, the locations of the extracellular tips for class B glucagon receptors allow for a much wider and deeper binding cavity in the [https://en.wikipedia.org/wiki/Ligand_(biochemistry) ligand-binding pocket], which is much more immense than any of the class A GCGRs <ref name="Tips">PMID: 23863937</ref>. These wide ranges specifically occur between two sets of alpha helices, as seen in '''Figure 2''' below.
@@ Line 25: / Line 25: @@
 Many of the [https://en.wikipedia.org/wiki/Residue_(chemistry) residues] that are in direct contact with the glucagon molecule are [https://en.wikipedia.org/wiki/Ion charged] or are [https://en.wikipedia.org/wiki/Chemical_polarity polar].
 [[Image:Screen Shot 2016-03-29 at 3.24.43 PM.png|(|):|400 px|right|thumb|'''Figure 4: Salt Bridge'''. The salt bridge is located on the intracellular side at the bottom of the protein, in relation to the orientation it holds within the cell membrane. It is made between residues Glu 406, Arg 173, and Arg 346, as labeled in the figure.]]
-There are also many smaller residues on glucagon that support the bulky residues on the GCGR. These residues are located within the <scene name='72/721535/Binding_pocket_orange/1'>binding pocket</scene> of the 7TM <ref name="Ligands">PMID: 21542831</ref>. There are specific amino acid interactions that hold the helices of the 7TM in the closed conformation that maximizes [http://www.chemicool.com/definition/affinity.html affinity]. This includes a [https://en.wikipedia.org/wiki/Disulfide disulfide bond] between <scene name='72/721535/Disulfide_bond_notspin/1'>Cys 294 and Cys 224</scene> mentioned earlier that serves to hold the ECL1 and ECL2 in the proper orientation. Additionally, the [https://en.wikipedia.org/wiki/Salt_bridge_%28protein_and_supramolecular%29 salt bridges] between Glu 406, Arg 173, and Arg 346, also mentioned earlier, hold the conformation together for higher affinity. Finally, alpha helical structure of the <scene name='72/721535/Opening_orientation/2'>stalk</scene> is imperative to the affinity and binding of the glucagon <ref name="Tips">PMID: 23863937</ref>.
+There are also many smaller residues on glucagon that support the bulky residues on the GCGR. These residues are located within the <scene name='72/721535/Binding_pocket_orange/1'>binding pocket</scene> of the 7TM <ref name="Ligands">PMID: 21542831</ref>. There are specific amino acid interactions that hold the helices of the 7TM in the closed conformation that maximizes [http://www.chemicool.com/definition/affinity.html affinity]. This includes a [https://en.wikipedia.org/wiki/Disulfide disulfide bond] between <scene name='72/721535/Disulfide_bond_notspin/1'>Cys 294 and Cys 224</scene> mentioned earlier that serves to hold the ECL1 and ECL2 in the proper orientation. Additionally, the [https://en.wikipedia.org/wiki/Salt_bridge_%28protein_and_supramolecular%29 salt bridges] between Glu 406, Arg 173, and Arg 346, also mentioned earlier, hold the conformation together for higher affinity. Finally, alpha helical structure of the stalk is imperative to the affinity and binding of the glucagon <ref name="Tips">PMID: 23863937</ref>.