Sandbox Reserved 1165: Difference between revisions

In comparison, class A vs. class B glucagon receptors share less than fifteen percent sequence homology, but both share this 7TM domain. <ref name="Intro">PMID: 24359917</ref> Understanding for class A family of GCGRs for the 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 but has recently started catching up. <ref name="Tips">PMID: 23863937</ref> Comparison of the <scene name='72/721536/7tm/2'>Class B GCGR 7TM</scene> to that of a <scene name='72/721536/Class_a/1'>class A 7TM</scene> showed that the general orientation and positioning of the [https://en.wikipedia.org/wiki/Alpha_helix alpha helices] are conserved through both classes. Detailed structural alignments of the two GPCR subclasses 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 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 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 Arg] 173 and Arg 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 <scene name='72/721535/Disulfide_bond_notspin/1'> Cys 294 and Cys 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 [https://en.wikipedia.org/wiki/Ligand_(biochemistry) ligand-binding pocket] than any of the class A GPCRs <ref name="Tips">PMID: 23863937</ref>. These wide extracellular tip locations specifically occur between two sets of alpha helices, (Figure 2).