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Structure of Class B Human Glucagon G-Protein Coupled Receptors (GCGRs)

G protein coupled receptors (GPCRs) are recognized as the largest known class of integral membrane proteins and are divided into five families; the rhodopsin family (class A), the secretin family (class B), the adhesion family, the glutamate family (class C), and the frizzled/taste family (class F). Roughly 5% of the human genome encodes g-protein-coupled receptors which are responsible for the transduction of endogenous signals and the instigation of cellular response. The variants all contain a similar seven α-helical transmembrane domain (TMD) that, once bound to its peptide ligand, undergoes conformational change and tranduces a signal to coupled, heterotrimeric G proteins which initiate intracellular signal pathways and generate physiological and pathological processes. ^[1]

Class B GPCRs contain 15 distinct receptors for peptide hormones and generate their signal pathway through the activation of adenylate cyclase (AC) which increases concentration of cAMP, inositol phosphate, and calcium levels in cyto. ^[2] These signals are essential elements of intracellular signal cascades for human diseases including type II diabetes mellitus, osteoporosis, obesity, cancer, neurological degeneration, cardiovascular diseases, headaches, and psychiatric disorders; making their regulation through drug targeting of particular interest to companies developing novel molecules. ^[3] Structurally based approaches to the development of small-molecule agonists and antagonists have been hampered by the lack of accurate Class B TMD visualizations until recent crystal structures of corticoptropin-releasing factor receptor 1 and human glucagon were realized. ^{[4] [5]}

The glucagon class B GPCR (GCGR) is involved in glucose homeostasis through the binding of the signal peptide glucagon.

spinqualitylabelsall models 7TM Helical Structure of 4L6R GPCR Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image This is a default text for your page Allie Paton/Sandbox 1181. Click above on http://sbkb.org/fs/glucagon-receptor to modify. Be careful with the < and > signs. You may include any references to papers as in: using DOI # [6] or to the article describing Jmol [7] to the rescue. Contents 1 Introduction 2 Comparisons to other G proteins 2.1 Structural similarities AND DIFFERENCES between class A and class B GPCRs 2.2 Sequential similarities 3 Functions of Glucagon receptor 3.1 Peptide binding and selectivity 3.2 Conformational changes 3.3 Signaling pathway involvement 4 Kinetics 5 Ligand specifics 5.1 Peptide specifics 5.2 Active binding domains/sites 5.3 Biological function of glucagon 5.4 Signaling pathways 6 Clinical relevance 6.1 Future research direction 6.2 Current drug targets 6.3 Possible structural considerations for agonists 7 Relevance 7.1 Class B in Comparison to Class A 7.1.1 Structural Similarities 7.1.2 Sequential Similarities 7.2 Current Drug Targets Introduction Glucagon is released from pancreatic α-cells when blood glucose levels fall after a period of fasting or several hours following intake of dietary carbohydrates. Once the peptide hormone is released, it binds to GCGRs initiating signaling to heterotrimeric G-proteins containing Gαs. [8] Additionally, GCGR can regulate additional signal pathways including G-proteins of the Gαi family through the adoption of differing receptor conformations. [9] Comparisons to other G proteins The class B GPCR GCGR is different from other Class A GPCRs in several ways. The first is that GCGR has a protrusion known as a 'stalk' which is a three helical turn elongation of the N-terminus that protrudes past the extracellular (EC) membrane. ((CAN WE INSERT LINK TO 2D PIC HERE??)) Secondly, the extracellular loop 1 (ECL1) is 3-4 times longer than comparable loops in class A GPCRs. Through mutagenesis studies, the stalk and ECL1 have been determined to affect ligand-receptor interaction. [10] ((INSERT 2D PIC OF STALK ACTIVE RESIDUES AND ECL1 ACTIVE RESIDUES)) Most notably, GCGR contains a prominent central splay which is solvent filled and accessible from the extracellular side. This central splay is notably absent from class A GPCRs and represents a tantalizing target for agonists/antagonists and is the focus of much current research into GCGR signal regulation. [11] Structural similarities AND DIFFERENCES between class A and class B GPCRs ((CAN WE TURN PICS INTO LINKS OR SMALLER IMAGES???)) Similarities between Class A and Sequential similarities ALLIE'S Snake Chain Functions of Glucagon receptor Peptide binding and selectivity from presentation Conformational changes Signaling pathway involvement Textbook Reference Kinetics Ligand specifics Peptide specifics Active binding domains/sites Biological function of glucagon Glucagon serves three main functions: Regulation of cholesterol production Energetically intense process Downregulates cholesterol production by stimulating phosphorylation of HMG-CoA Inactivates HMG-CoA Fatty acid mobilization Glucagon affects adipose tissue Activates TAG breakdown cAMP dependent phosphorylation of perilipin and hormone sensitive lipases Fatty acid exported to liver and other tissues for energy use More glucose available for brain use Increases blood glucose levels Lowers the concentration of fructose 2,6-bisphospate in blood – allosteric inhibitor of the gluconeogenic enzyme fructose 1,6-bisphosphotase Activates phosphofructose kinase 1 – glycolytic enzyme increases glucose levels (Nelson & Cox, Principles of Biochemistry, 2008) Signaling pathways GCGR signals generate downstream signals predominantly through the increase of intracellular cAMP, however there are other pathways being uncovered that are the result of GCGR adopting multiple, active conformations. Researchers are currently investigating how receptor activity-modifying proteins interact with the ligand and GCGR in which the signaling bias of the receptor is altered. [12] Clinical relevance Future research direction Current drug targets See “Landmark studies on the glucagon subfamily of GPCRs: from small molecule modulators to a crystal structure” good clinical references and small molecule target tables Possible structural considerations for agonists (our distance measurements and shape analysis images) Also see Landmark studies on the glucagon subfamily of GPCRs: from small molecule modulators to a crystal structure Relevance Class B in Comparison to Class A Figure Legend Structural Similarities Sequential Similarities Current Drug Targets This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

References

1. ↑ Zhang Y, Devries ME, Skolnick J. Structure modeling of all identified G protein-coupled receptors in the human genome. PLoS Comput Biol. 2006 Feb;2(2):e13. Epub 2006 Feb 17. PMID:16485037 doi:http://dx.doi.org/10.1371/journal.pcbi.0020013
2. ↑ Bortolato A, Dore AS, Hollenstein K, Tehan BG, Mason JS, Marshall FH. Structure of Class B GPCRs: new horizons for drug discovery. Br J Pharmacol. 2014 Jul;171(13):3132-45. doi: 10.1111/bph.12689. PMID:24628305 doi:http://dx.doi.org/10.1111/bph.12689
3. ↑ Hollenstein K, de Graaf C, Bortolato A, Wang MW, Marshall FH, Stevens RC. Insights into the structure of class B GPCRs. Trends Pharmacol Sci. 2014 Jan;35(1):12-22. doi: 10.1016/j.tips.2013.11.001. Epub, 2013 Dec 18. PMID:24359917 doi:http://dx.doi.org/10.1016/j.tips.2013.11.001
4. ↑ Hollenstein K, Kean J, Bortolato A, Cheng RK, Dore AS, Jazayeri A, Cooke RM, Weir M, Marshall FH. Structure of class B GPCR corticotropin-releasing factor receptor 1. Nature. 2013 Jul 25;499(7459):438-43. doi: 10.1038/nature12357. Epub 2013 Jul 17. PMID:23863939 doi:http://dx.doi.org/10.1038/nature12357
5. ↑ Siu FY, He M, de Graaf C, Han GW, Yang D, Zhang Z, Zhou C, Xu Q, Wacker D, Joseph JS, Liu W, Lau J, Cherezov V, Katritch V, Wang MW, Stevens RC. Structure of the human glucagon class B G-protein-coupled receptor. Nature. 2013 Jul 25;499(7459):444-9. doi: 10.1038/nature12393. Epub 2013 Jul 17. PMID:23863937 doi:10.1038/nature12393
6. ↑ Siu FY, He M, de Graaf C, Han GW, Yang D, Zhang Z, Zhou C, Xu Q, Wacker D, Joseph JS, Liu W, Lau J, Cherezov V, Katritch V, Wang MW, Stevens RC. Structure of the human glucagon class B G-protein-coupled receptor. Nature. 2013 Jul 25;499(7459):444-9. doi: 10.1038/nature12393. Epub 2013 Jul 17. PMID:23863937 doi:10.1038/nature12393
7. ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
8. ↑ Ahren B. Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes. Nat Rev Drug Discov. 2009 May;8(5):369-85. doi: 10.1038/nrd2782. Epub 2009 Apr, 14. PMID:19365392 doi:http://dx.doi.org/10.1038/nrd2782
9. ↑ Xu Y, Xie X. Glucagon receptor mediates calcium signaling by coupling to G alpha q/11 and G alpha i/o in HEK293 cells. J Recept Signal Transduct Res. 2009 Dec;29(6):318-25. doi:, 10.3109/10799890903295150. PMID:19903011 doi:http://dx.doi.org/10.3109/10799890903295150
10. ↑ Siu FY, He M, de Graaf C, Han GW, Yang D, Zhang Z, Zhou C, Xu Q, Wacker D, Joseph JS, Liu W, Lau J, Cherezov V, Katritch V, Wang MW, Stevens RC. Structure of the human glucagon class B G-protein-coupled receptor. Nature. 2013 Jul 25;499(7459):444-9. doi: 10.1038/nature12393. Epub 2013 Jul 17. PMID:23863937 doi:10.1038/nature12393
11. ↑ doi: https://dx.doi.org/10.1016/j.tips.2013.11.001.
12. ↑ Weston C, Lu J, Li N, Barkan K, Richards GO, Roberts DJ, Skerry TM, Poyner D, Pardamwar M, Reynolds CA, Dowell SJ, Willars GB, Ladds G. Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2). J Biol Chem. 2015 Sep 18;290(38):23009-22. doi: 10.1074/jbc.M114.624601. Epub, 2015 Jul 21. PMID:26198634 doi:http://dx.doi.org/10.1074/jbc.M114.624601

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