Sandbox Reserved 1165: Difference between revisions

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===Introduction===

[[Image:Screen_Shot_2016-03-29_at_12.45.02_PM.png|(|):|200 px|right|thumb|<font size="1.0"><div style="text-align: center;">'''Figure 1: Glucagon''', shown in green, bound to its receptor in the class B family </div></font>]]

'''Human glucagon class B G protein-coupled receptors (GPCRs'''), also known as [https://en.wikipedia.org/wiki/Secretin_receptor_family secretin-like receptors], are a subfamily of the more well known class A ([https://en.wikipedia.org/wiki/Rhodopsin-like_receptors rhodopsin-like]) glucagon receptor family<ref name="Intro">PMID: 24359917</ref> . Located in the [https://en.wikipedia.org/wiki/Liver liver], class B glucagon receptors (GCGRs) are activated by the binding of the hormonal peptide [https://en.wikipedia.org/wiki/Glucagon glucagon] (Figure 1)~~, which~~ leads to the release of [https://en.wikipedia.org/wiki/Glucose glucose] into the [https://en.wikipedia.org/wiki/Circulatory_system bloodstream] and plays an essential role in [https://en.wikipedia.org/wiki/Blood_sugar_regulation glucose homeostasis]. Class B GCGRs are composed of a [https://en.wikipedia.org/wiki/Liver seven transmembrane domain] (7TM) and [https://en.wikipedia.org/wiki/Liver extracellular domain] (ECD) that are ~~of vital importance in~~ glucagon binding. In comparison, class A vs. class B glucagon receptors share less than fifteen percent sequence homology, but both share this 7TM which is a primary area of comparison between the two <ref name="Intro">PMID: 24359917</ref>. The understanding of class A family of GCGRs structure-function [https://en.wikibooks.org/wiki/Structural_Biochemistry/Enzyme_Catalytic_Mechanism mechanism] has made great progress over the past few years, but understanding of class B has fallen behind.

'''Human glucagon class B G protein-coupled receptors (GPCRs'''), also known as [https://en.wikipedia.org/wiki/Secretin_receptor_family secretin-like receptors], are a subfamily GPCRs and very similar in structure to the more well known class A ([https://en.wikipedia.org/wiki/Rhodopsin-like_receptors rhodopsin-like]) glucagon receptor family. <ref name="Intro">PMID: 24359917</ref> Located in the [https://en.wikipedia.org/wiki/Liver liver], class B glucagon receptors (GCGRs) are activated by the binding of the hormonal peptide [https://en.wikipedia.org/wiki/Glucagon glucagon] (Figure 1). Glucagon binding leads to the release of [https://en.wikipedia.org/wiki/Glucose glucose] into the [https://en.wikipedia.org/wiki/Circulatory_system bloodstream] and plays an essential role in [https://en.wikipedia.org/wiki/Blood_sugar_regulation glucose homeostasis]. Class B GCGRs are composed of a [https://en.wikipedia.org/wiki/Liver seven transmembrane domain] (7TM) and [https://en.wikipedia.org/wiki/Liver extracellular domain] (ECD) that are required for glucagon binding.

=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 <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 <scene name='72/721536/Helix_eight_tilt/2'>helix VIII tilt</scene> 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, (Figure 2).

In comparison, class A vs. class B glucagon receptors share less than fifteen percent sequence homology, but both share this 7TM which is a primary area of comparison between the two. <ref name="Intro">PMID: 24359917</ref> The understanding of class A family of GCGRs structure-function [https://en.wikibooks.org/wiki/Structural_Biochemistry/Enzyme_Catalytic_Mechanism mechanism] has made great progress over the past few years, but understanding of class B has fallen behind. 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 <scene name='72/721536/Helix_eight_tilt/2'>helix VIII tilt</scene> 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, (Figure 2).

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@@ Line 4: / Line 4: @@
 ===Introduction===
 [[Image:Screen_Shot_2016-03-29_at_12.45.02_PM.png|(|):|200 px|right|thumb|<font size="1.0"><div style="text-align: center;">'''Figure 1: Glucagon''', shown in green, bound to its receptor in the class B family </div></font>]]
-'''Human glucagon class B G protein-coupled receptors (GPCRs'''), also known as [https://en.wikipedia.org/wiki/Secretin_receptor_family secretin-like receptors], are a subfamily of the more well known class A ([https://en.wikipedia.org/wiki/Rhodopsin-like_receptors rhodopsin-like]) glucagon receptor family<ref name="Intro">PMID: 24359917</ref> . Located in the [https://en.wikipedia.org/wiki/Liver liver], class B glucagon receptors (GCGRs) are activated by the binding of the hormonal peptide [https://en.wikipedia.org/wiki/Glucagon glucagon] (Figure 1), which leads to the release of [https://en.wikipedia.org/wiki/Glucose glucose] into the [https://en.wikipedia.org/wiki/Circulatory_system bloodstream] and plays an essential role in [https://en.wikipedia.org/wiki/Blood_sugar_regulation glucose homeostasis]. Class B GCGRs are composed of a [https://en.wikipedia.org/wiki/Liver seven transmembrane domain] (7TM) and [https://en.wikipedia.org/wiki/Liver extracellular domain] (ECD) that are of vital importance in glucagon binding. In comparison, class A vs. class B glucagon receptors share less than fifteen percent sequence homology, but both share this 7TM which is a primary area of comparison between the two <ref name="Intro">PMID: 24359917</ref>. The understanding of class A family of GCGRs structure-function [https://en.wikibooks.org/wiki/Structural_Biochemistry/Enzyme_Catalytic_Mechanism mechanism] has made great progress over the past few years, but understanding of class B has fallen behind.
+'''Human glucagon class B G protein-coupled receptors (GPCRs'''), also known as [https://en.wikipedia.org/wiki/Secretin_receptor_family secretin-like receptors], are a subfamily GPCRs and very similar in structure to the more well known class A ([https://en.wikipedia.org/wiki/Rhodopsin-like_receptors rhodopsin-like]) glucagon receptor family. <ref name="Intro">PMID: 24359917</ref> Located in the [https://en.wikipedia.org/wiki/Liver liver], class B glucagon receptors (GCGRs) are activated by the binding of the hormonal peptide [https://en.wikipedia.org/wiki/Glucagon glucagon] (Figure 1). Glucagon binding leads to the release of [https://en.wikipedia.org/wiki/Glucose glucose] into the [https://en.wikipedia.org/wiki/Circulatory_system bloodstream] and plays an essential role in [https://en.wikipedia.org/wiki/Blood_sugar_regulation glucose homeostasis]. Class B GCGRs are composed of a [https://en.wikipedia.org/wiki/Liver seven transmembrane domain] (7TM) and [https://en.wikipedia.org/wiki/Liver extracellular domain] (ECD) that are required for glucagon binding.
 =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 <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 <scene name='72/721536/Helix_eight_tilt/2'>helix VIII tilt</scene> 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, (Figure 2).
+In comparison, class A vs. class B glucagon receptors share less than fifteen percent sequence homology, but both share this 7TM which is a primary area of comparison between the two. <ref name="Intro">PMID: 24359917</ref> The understanding of class A family of GCGRs structure-function [https://en.wikibooks.org/wiki/Structural_Biochemistry/Enzyme_Catalytic_Mechanism mechanism] has made great progress over the past few years, but understanding of class B has fallen behind. 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 <scene name='72/721536/Helix_eight_tilt/2'>helix VIII tilt</scene> 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, (Figure 2).