Sandbox Reserved 1165: Difference between revisions

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.

For glucagon to initiate the breakdown of [https://en.wikipedia.org/wiki/Glycogen glycogen] into glucose, it follows a specific [https://en.wikipedia.org/wiki/Glucagon signaling mechanism]. Glucagon binds to a G protein-coupled receptor located on the [https://en.wikipedia.org/wiki/Cell_membrane plasma membrane], and this binding induces a [https://en.wikipedia.org/wiki/Conformational_change conformational change] that activates G proteins which exchanges a [https://en.wikipedia.org/wiki/Guanosine_diphosphate guanosine diphosphate (GDP]) for guanosine [https://en.wikipedia.org/wiki/Guanosine_triphosphate triphosphate (GTP)] that is bound to the [https://en.wikipedia.org/wiki/G_alpha_subunit alpha subunit]. Now with the GTP in place, the activated alpha subunit leaves the [https://en.wikipedia.org/wiki/Heterotrimeric_G_protein heterotrimeric G protein] and activatesthe next [https://en.wikipedia.org/wiki/Enzyme enzyme] in the cascade, [https://en.wikipedia.org/wiki/Adenylyl_cyclase adenylate cyclase]. Once adenylate cyclase is activated, it catalyzes the conversion of [https://en.wikipedia.org/wiki/Adenosine_triphosphate adenosine triphosphate (ATP)] into cyclic [https://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphate adenosine monophosphate (cAMP)]. This in turn activates [https://en.wikipedia.org/wiki/Protein_kinase_A protein kinase A (PKA)] that then activates [https://en.wikipedia.org/wiki/Phosphorylase_kinase phosphorylase kinase]. Finally, the phosphorylase kinase [https://en.wikipedia.org/wiki/Phosphorylation phosphorylates] [https://en.wikipedia.org/wiki/Glycogen_phosphorylase glycogen phosphorylase b] that is then turned into its activated form, glycogen phosphorylase a. This phosphorylase A enzyme is responsible for catalyzing the release of [https://en.wikipedia.org/wiki/Glucose_1-phosphate glucose-1-phosphate] into the bloodstream from glycogen [https://en.wikipedia.org/wiki/Polymer polymers].