User:Dean Williams/Sandbox 1180
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
==Structure of Class B Human Glucagon G-Protein Coupled Receptors (GCGRs)== | ==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. <ref>DOI 10.1371/journal.pcbi.0020013</ref> | + | 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 or 7TMD) 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. <ref>DOI 10.1371/journal.pcbi.0020013</ref> |
| - | 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. <ref>DOI 10.1111/bph.12689</ref> 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. <ref name= "Hollenstein 2014">DOI 10.1016/j.tips.2013.11.001</ref> 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. <ref>DOI 10.1038/nature12357</ref> <ref name= "Siu 2013">DOI 10.1038/nature12393</ref> | + | 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. <ref>DOI 10.1111/bph.12689</ref> 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. <ref name= "Hollenstein 2014">DOI 10.1016/j.tips.2013.11.001</ref> 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. <ref name= "Hollenstein 2013">DOI 10.1038/nature12357</ref> <ref name= "Siu 2013">DOI 10.1038/nature12393</ref> |
The glucagon class B GPCR (GCGR) is involved in glucose homeostasis through the binding of the signal peptide glucagon. | The glucagon class B GPCR (GCGR) is involved in glucose homeostasis through the binding of the signal peptide glucagon. | ||
| Line 12: | Line 12: | ||
| - | + | ||
| - | + | ||
== Introduction == | == 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 GCGR which is a 485 amino acid protein found in the liver, kidney, intestinal smooth muscle, brain, and adipose | + | 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 GCGR which is a 485 amino acid protein found in the liver, kidney, intestinal smooth muscle, brain, and adipose tissues. <ref name= "Yang 2015">DOI 10.1038/aps.2015.78</ref> Upon binding, signaling is initiated to heterotrimeric G-proteins containing Gαs. <ref name= "Ahren 2009">DOI 10.1038/nrd2782</ref> Additionally, GCGR can regulate additional signal pathways including G-proteins of the Gαi family through the adoption of differing receptor conformations. <ref name= "Xu 2009">DOI 10.3109/10799890903295150</ref> |
| - | == | + | ==Structural Considerations== |
| - | + | ||
| - | === | + | ===Comparison between Class A and Class B GPCRs=== |
| - | (( | + | The class B GPCRs, of which GCGR is a member, are different from other Class A GPCRs in several ways. The first is that class B GPCRs contain a protrusion known as a 'stalk,' which is a three α-helical turn elongation of the N-terminus that protrudes past the extracellular (EC) membrane. Structural integrity of this domain in GCGR is essential to ligand binding affinity. [[Image:ALA135PRO stalk unwinding.png|100 px|left|thumb|Figure Legend]] [[Image:Gln142 Tyr138 Glucagon interaction.png|100 px|left|thumb|Figure Legend]] Secondly, the extracellular loop 1 (ECL1) is 3-4 times longer than comparable loops in class A GPCRs, and also affects ligand binding affinity. [[Image:Asn_298__Trp_295.png|100 px|left|thumb|Figure Legend: Active sites linked to glucagon binding affinity located on ECL1 are labeled]] <ref name= "Siu 2013"/> Most notably, class B GPCRs contain a prominent central splay which is solvent filled and accessible from the extracellular side. This central splay is notably absent from class A GPCRs, represents a tantalizing target for agonists/antagonists, and is the focus of much current research into GCGR signal regulation. <ref name= "Hollenstein 2014"/> |
Similarities between Class A [[Image:Beta2 class A and Glucagon class B receptors aligned.png |100 px|left|thumb|Figure Legend]] <scene name='72/727091/B2-adrenergic_glucagon_aligned/9'>TextToBeDisplayed</scene> and [[Image:Corticotropin class B and Glucagon class B receptors aligned.png |100 px|left|thumb|Figure Legend]] <scene name='72/727091/Corticotropin_glucagon_aligned/1'>Two Class B protein receptors showing central splay</scene> | Similarities between Class A [[Image:Beta2 class A and Glucagon class B receptors aligned.png |100 px|left|thumb|Figure Legend]] <scene name='72/727091/B2-adrenergic_glucagon_aligned/9'>TextToBeDisplayed</scene> and [[Image:Corticotropin class B and Glucagon class B receptors aligned.png |100 px|left|thumb|Figure Legend]] <scene name='72/727091/Corticotropin_glucagon_aligned/1'>Two Class B protein receptors showing central splay</scene> | ||
| - | ===Structurally Significant | + | ===Structurally Significant GCGR 7TDM Residues=== |
| - | [[Image:Protter GLR HUMAN.png |100 px|left|thumb|Snake Plot of GCGR TMD]] | + | [[Image:Protter GLR HUMAN.png |100 px|left|thumb|Snake Plot of GCGR TMD<ref name= "Siu 2013"/>]] |
| Line 36: | Line 34: | ||
| + | The snake plot shows the conservation and effects of mutagenesis in the 7TMD structure of class B human GPCR. The highly conserved amino acids imply an importance to that functioning of the individual residues and their interactions. The amino acids which have a great impact on the function of the receptor are highlighted in teal, yellow, and black, and offer evidence that the position and interaction of the amino acid is crucial for protein function. Most of the residues that play an important role in glucagon binding face the main cavity of the 7TM structure. Mutagenesis in these positions highly compromises the functioning of the glucagon binding. | ||
| - | ==Functions of Glucagon receptor== | + | |
| + | |||
| + | |||
| + | |||
| + | |||
| + | |||
| + | |||
| + | |||
| + | |||
| + | |||
| + | |||
| + | |||
| + | |||
| + | |||
| + | |||
| + | |||
| + | |||
| + | |||
| + | |||
| + | |||
| + | |||
| + | |||
| + | ==Functions of Glucagon receptor (GCGR)== | ||
===Peptide binding and selectivity=== | ===Peptide binding and selectivity=== | ||
| - | + | It has been discovered that the large, soluble N-terminal extracellular domains (ECD) of GCGR are primary in ligand selectivity with the deep, ligand pocket of the TMD providing secondary recognition. <ref name= "Yang 2015"/> [[Image:Movie_Frame_2.png|100 px|left|thumb|Figure Legend]] | |
===Conformational changes=== | ===Conformational changes=== | ||
| + | Because of the difficulty of stabilizing and crystallizing Class B TMDs, very little is known about the conformational changes that transduce cell signals endogenously. It is known that GCGR can regulate additional signal pathways including G-proteins of the Gαi family through the adoption of differing receptor conformations, but research is ongoing. <ref name= "Xu 2009"/> | ||
| - | ===Signaling | + | |
| - | + | ===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 (RAMPs) interact with the ligand and GCGR in which the signaling bias of the receptor is altered. <ref>DOI 10.1074/jbc.M114.624601</ref> | ||
| + | |||
==Kinetics== | ==Kinetics== | ||
GPCR activity is regularly quantified by ligand binding affinity, potency, efficacy, and kinetics. These measurement are used to measure drug ligand interactions in vivo. Recently, GPCRs have been crystallized and catalogued, which tend to include a need to stabilize the receptor, emphasizing the instability of the G coupled protein receptor. Zhang et. al. imply the importance of receptor folding in the cell membrane, in the human class B GPCR the 7TM portion, for receptor stability and function. <ref>DOI 10.1016/j.tibs.2014.12.005</ref> | GPCR activity is regularly quantified by ligand binding affinity, potency, efficacy, and kinetics. These measurement are used to measure drug ligand interactions in vivo. Recently, GPCRs have been crystallized and catalogued, which tend to include a need to stabilize the receptor, emphasizing the instability of the G coupled protein receptor. Zhang et. al. imply the importance of receptor folding in the cell membrane, in the human class B GPCR the 7TM portion, for receptor stability and function. <ref>DOI 10.1016/j.tibs.2014.12.005</ref> | ||
| Line 70: | Line 94: | ||
===Active binding domains/sites=== | ===Active binding domains/sites=== | ||
| + | |||
[[Image:Movie Frame 8.png |100 px|left|thumb|Figure Legend]] | [[Image:Movie Frame 8.png |100 px|left|thumb|Figure Legend]] | ||
[[Image:Movie Frame 3.png |100 px|left|thumb|Figure Legend<ref name= "Siu 2013"/>]] | [[Image:Movie Frame 3.png |100 px|left|thumb|Figure Legend<ref name= "Siu 2013"/>]] | ||
| Line 76: | Line 101: | ||
| - | |||
| - | ===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. <ref>DOI 10.1074/jbc.M114.624601</ref> | ||
==Clinical relevance== | ==Clinical relevance== | ||
| Line 90: | Line 112: | ||
===Current drug targets=== | ===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 | 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 | ||
| + | |||
| + | [[Image:Small molecule modulators Page 1.jpg|100 px|left|thumb|Figure Legend]] | ||
| + | [[Image:Small molecule modulators Page 2.jpg|100 px|left|thumb|Figure Legend]] | ||
===Possible structural considerations for agonists=== | ===Possible structural considerations for agonists=== | ||
| Line 96: | Line 121: | ||
| - | |||
| - | |||
| - | == Relevance == | ||
| - | === Class B in Comparison to Class A === | ||
| - | [[Image:Class B.png |100 px|left|thumb|Figure Legend]] | ||
| - | ==== Structural Similarities ==== | ||
| - | ==== Sequential Similarities ==== | ||
| - | === Current Drug Targets === | ||
Revision as of 20:43, 1 April 2016
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 or 7TMD) 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.
| |||||||||||
References
- ↑ 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
- ↑ 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
- ↑ 3.0 3.1 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
- ↑ 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
- ↑ 5.0 5.1 5.2 5.3 5.4 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
- ↑ 6.0 6.1 Yang DH, Zhou CH, Liu Q, Wang MW. Landmark studies on the glucagon subfamily of GPCRs: from small molecule modulators to a crystal structure. Acta Pharmacol Sin. 2015 Sep;36(9):1033-42. doi: 10.1038/aps.2015.78. Epub 2015, Aug 17. PMID:26279155 doi:http://dx.doi.org/10.1038/aps.2015.78
- ↑ 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
- ↑ 8.0 8.1 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
- ↑ 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
- ↑ Zhang X, Stevens RC, Xu F. The importance of ligands for G protein-coupled receptor stability. Trends Biochem Sci. 2015 Feb;40(2):79-87. doi: 10.1016/j.tibs.2014.12.005. Epub, 2015 Jan 15. PMID:25601764 doi:http://dx.doi.org/10.1016/j.tibs.2014.12.005
- ↑ 'Lehninger A., Nelson D.N, & Cox M.M. (2008) Lehninger Principles of Biochemistry. W. H. Freeman, fifth edition.'
- ↑ 12.0 12.1 Salon JA, Lodowski DT, Palczewski K. The significance of G protein-coupled receptor crystallography for drug discovery. Pharmacol Rev. 2011 Dec;63(4):901-37. doi: 10.1124/pr.110.003350. PMID:21969326 doi:http://dx.doi.org/10.1124/pr.110.003350
