User:Dean Williams/Sandbox 1180
From Proteopedia
(Difference between revisions)
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==Comparisons to other G proteins== | ==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. <ref>DOI 10.1038/nature12393</ref> ((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. <ref name= "Hollenstein 2014"> | + | 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. <ref>DOI 10.1038/nature12393</ref> ((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. <ref name= "Hollenstein 2014"/> |
===Structural similarities AND DIFFERENCES between class A and class B GPCRs=== | ===Structural similarities AND DIFFERENCES between class A and class B GPCRs=== | ||
((CAN WE TURN PICS INTO LINKS OR SMALLER IMAGES???)) | ((CAN WE TURN PICS INTO LINKS OR SMALLER IMAGES???)) | ||
| - | Similarities between Class A [[Image:Beta2 class A and Glucagon class B receptors aligned.png]]<scene name='72/727091/B2-adrenergic_glucagon_aligned/9'>TextToBeDisplayed</scene> and [[Image:Corticotropin class B and Glucagon class B receptors aligned.png]]<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 TMD Residues=== | ===Structurally Significant TMD 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]] |
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<ref name = 'Lehninger'>'Lehninger A., Nelson D.N, & Cox M.M. (2008) Lehninger Principles of Biochemistry. W. H. Freeman, fifth edition.' </ref> | <ref name = 'Lehninger'>'Lehninger A., Nelson D.N, & Cox M.M. (2008) Lehninger Principles of Biochemistry. W. H. Freeman, fifth edition.' </ref> | ||
| - | (Nelson & Cox, Principles of Biochemistry, 2008) | ||
===Glucagon Peptide Stability and Active Binding Sites=== | ===Glucagon Peptide Stability and Active Binding Sites=== | ||
| - | Essential, conserved residues of glucagon, as discovered through mutagenesis and photo cross-linking studies have been labeled and colored in red. <ref name= "Siu 2013"> <scene name='72/727091/Glucagon_important_residues/2'>Important stability/active sites | + | Essential, conserved residues of glucagon, as discovered through mutagenesis and photo cross-linking studies have been labeled and colored in red. <ref name= "Siu 2013"> <scene name='72/727091/Glucagon_important_residues/2'>Important stability/active sites</scene> |
| - | <scene name='72/727091/Glucagon_important_residues/2'>Important stability/active sites <ref>DOI 10.1038/nature12393</ref></scene> | ||
===Active binding domains/sites=== | ===Active binding domains/sites=== | ||
| - | [[Image:Movie Frame 8.png]][[Image:Movie Frame 3.png]][[Image:Movie Frame 6.png]][[Image:Glucagon with Q3 and N-terminus.png]] | + | [[Image:Movie Frame 8.png |100 px|left|thumb|Figure Legend]][[Image:Movie Frame 3.png |100 px|left|thumb|Figure Legend]][[Image:Movie Frame 6.png |100 px|left|thumb|Figure Legend]][[Image:Glucagon with Q3 and N-terminus.png |100 px|left|thumb|Figure Legend]] |
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===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 | |
| - | + | ||
| - | target tables | + | |
===Possible structural considerations for agonists=== | ===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 | |
| - | + | ||
| - | molecule modulators to a crystal structure | + | |
Revision as of 18:45, 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) 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.
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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 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
