Sandbox Reserved 1165: Difference between revisions

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=Human Glucagon Class B G Protein-Coupled Receptors (GPCRs)=

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[[Image:Screen_Shot_2016-03-22_at_5.28.03_PM.png|(|):|400 px|center|Binding Residues]]

=Clinical Relevancy=

Of the fifteen human class B GPCRs, eight have been identified as potential [https://en.wikipedia.org/wiki/Biological_target drug target]<ref name="Drug">PMID: 24628305</ref>. [http://www.wisegeek.com/what-are-therapeutic-agents.htm Therapeutic agents] have been created from the peptides themselves within this protein, but overall [https://en.wikipedia.org/wiki/Pharmaceutical_industry pharmaceutical companies] have had difficulty creating agents that act on family B GPCRS. There is an outward appearance and inherent flexibility in the class B GCGR 7TM because of conserved hydrogen bonds that flank a [https://en.wikipedia.org/wiki/Glycine glycine] residue, and this structure along with the ECD and its role of interactions on the extracellular side of receptors may provide evidence to how class B receptors adjust its conformational spectra for various receptors. Researchers hope to show how these conformations can be utilized in potential treatments of a wide array [https://en.wikipedia.org/wiki/List_of_mental_disorders disorders].

==Potential Inhibitors==

Research for class B GCGR [https://en.wikipedia.org/wiki/Enzyme_inhibitor inhibitors] is primarily looking into [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric inhibitors] having the ability to target specific receptors in order to treat problems like stress disorders, managing excess glucose in the bloodstream, and also alternative mechanisms for treating [https://en.wikipedia.org/wiki/Migraine migraines] <ref name="Inhibitors">PMID: 24189067</ref>. Known inhibitors include [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibodies] which inhibit GCGR through an allosteric mechanism. The monoclonal antibodies bind to two different sites, the ECD opposite of the binding region and then the helical portion of the ECD as well. These antibodies did not interact with the binding sites, but overall this inhibitor shows further proof that the ECD is extremely important for proper functioning of human class B GCGRs <ref name="Last">PMID: 19305799</ref>.

===Research===

Determining the structure of class B GCGRs is a reason for its lack of advanced knowledge in the field, but X-ray crystallography and NMR have been the main processes performed and have had some success with it over the past couple years <ref name="Lastt">PMID: 26227798</ref>. X-ray crystallography displayed the crystal structure of ECDs of class B GPCRs in complex with their ligands along with the crystal structure of the 7TM. In addition to this, NMR has allowed the ability to directly understand structures of soluble amino-terminal domains of numerous members of the secretin-like family that bind peptide hormones. Primary sequences analysis have led to the finding of seven segments of eighteen or more relatively hydrophobic residues that are believed to represent transmembrane helices that take part in creating an intramembranous helical bundle <ref name="Lastt">PMID: 26227798</ref>. Also, mutagenesis has been used to determine which residues were necessary in maximizing affinity for glucagon, mutagenesis being the process of mutating certain residues and observing the effect on affinity. If a residue held little importance to the overall affinity, the mutation would show little change in affinity. Finally, the orientation and mechanism of the peptide interactions within these structures are studied using peptide structure-activity relationships (SAR), receptor and ligand fragments, chimeric receptors, site-directed mutagenesis, photochemical cross-linking, and molecular modeling <ref name="Lastt">PMID: 26227798</ref>.

</StructureSection>

~~==Clinical Relevancy==~~

Of the fifteen human class B GPCRs, eight have been identified as potential [https://en.wikipedia.org/wiki/Biological_target drug target]<ref name="Drug">PMID: 24628305</ref>. [http://www.wisegeek.com/what-are-therapeutic-agents.htm Therapeutic agents] have been created from the peptides themselves within this protein, but overall [https://en.wikipedia.org/wiki/Pharmaceutical_industry pharmaceutical companies] have had difficulty creating agents that act on family B GPCRS. There is an outward appearance and inherent flexibility in the class B GCGR 7TM because of conserved hydrogen bonds that flank a [https://en.wikipedia.org/wiki/Glycine glycine] residue, and this structure along with the ECD and its role of interactions on the extracellular side of receptors may provide evidence to how class B receptors adjust its conformational spectra for various receptors. Researchers hope to show how these conformations can be utilized in potential treatments of a wide array [https://en.wikipedia.org/wiki/List_of_mental_disorders disorders]. Research for class B GCGR [https://en.wikipedia.org/wiki/Enzyme_inhibitor inhibitors] is primarily looking into [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric inhibitors] having the ability to target specific receptors in order to treat problems like stress disorders, managing excess glucose in the bloodstream, and also alternative mechanisms for treating [https://en.wikipedia.org/wiki/Migraine migraines] <ref name="Inhibitors">PMID: 24189067</ref>. Known inhibitors include [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibodies] which inhibit GCGR through an allosteric mechanism. The monoclonal antibodies bind to two different sites, the ECD opposite of the binding region and then the helical portion of the ECD as well. These antibodies did not interact with the binding sites, but overall this inhibitor shows further proof that the ECD is extremely important for proper functioning of human class B GCGRs <ref name="Last">PMID: 19305799</ref>. Determining the structure of class B GCGRs is a reason for its lack of advanced knowledge in the field, but X-ray crystallography and NMR have been the main processes performed and have had some success with it over the past couple years <ref name="Lastt">PMID: 26227798</ref>. X-ray crystallography displayed the crystal structure of ECDs of class B GPCRs in complex with their ligands along with the crystal structure of the 7TM. In addition to this, NMR has allowed the ability to directly understand structures of soluble amino-terminal domains of numerous members of the secretin-like family that bind peptide hormones. Primary sequences analysis have led to the finding of seven segments of eighteen or more relatively hydrophobic residues that are believed to represent transmembrane helices that take part in creating an intramembranous helical bundle <ref name="Lastt">PMID: 26227798</ref>. Also, mutagenesis has been used to determine which residues were necessary in maximizing affinity for glucagon, mutagenesis being the process of mutating certain residues and observing the effect on affinity. If a residue held little importance to the overall affinity, the mutation would show little change in affinity. Finally, the orientation and mechanism of the peptide interactions within these structures are studied using peptide structure-activity relationships (SAR), receptor and ligand fragments, chimeric receptors, site-directed mutagenesis, photochemical cross-linking, and molecular modeling <ref name="Lastt">PMID: 26227798</ref>.

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 <StructureSection load='4l6r' size='350' side='right' caption='Class B 7TM' scene='72/721536/Space_fill_residues/1'>
 =Human Glucagon Class B G Protein-Coupled Receptors (GPCRs)=
@@ Line 29: / Line 28: @@
 [[Image:Screen_Shot_2016-03-22_at_5.28.03_PM.png|(|):|400 px|center|Binding Residues]]
+=Clinical Relevancy=
+Of the fifteen human class B GPCRs, eight have been identified as potential [https://en.wikipedia.org/wiki/Biological_target drug target]<ref name="Drug">PMID: 24628305</ref>. [http://www.wisegeek.com/what-are-therapeutic-agents.htm Therapeutic agents] have been created from the peptides themselves within this protein, but overall [https://en.wikipedia.org/wiki/Pharmaceutical_industry pharmaceutical companies] have had difficulty creating agents that act on family B GPCRS. There is an outward appearance and inherent flexibility in the class B GCGR 7TM because of conserved hydrogen bonds that flank a [https://en.wikipedia.org/wiki/Glycine glycine] residue, and this structure along with the ECD and its role of interactions on the extracellular side of receptors may provide evidence to how class B receptors adjust its conformational spectra for various receptors. Researchers hope to show how these conformations can be utilized in potential treatments of a wide array [https://en.wikipedia.org/wiki/List_of_mental_disorders disorders].
+==Potential Inhibitors==
+Research for class B GCGR [https://en.wikipedia.org/wiki/Enzyme_inhibitor inhibitors] is primarily looking into [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric inhibitors] having the ability to target specific receptors in order to treat problems like stress disorders, managing excess glucose in the bloodstream, and also alternative mechanisms for treating [https://en.wikipedia.org/wiki/Migraine migraines] <ref name="Inhibitors">PMID: 24189067</ref>. Known inhibitors include [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibodies] which inhibit GCGR through an allosteric mechanism. The monoclonal antibodies bind to two different sites, the ECD opposite of the binding region and then the helical portion of the ECD as well. These antibodies did not interact with the binding sites, but overall this inhibitor shows further proof that the ECD is extremely important for proper functioning of  human class B GCGRs <ref name="Last">PMID: 19305799</ref>.
+===Research===
+Determining the structure of class B GCGRs is a reason for its lack of advanced knowledge in the field, but X-ray crystallography and NMR have been the main processes performed and have had some success with it over the past couple years <ref name="Lastt">PMID: 26227798</ref>. X-ray crystallography displayed the crystal structure of ECDs of class B GPCRs in complex with their ligands along with the crystal structure of the 7TM. In addition to this, NMR has allowed the ability to directly understand structures of soluble amino-terminal domains of numerous members of the secretin-like family that bind peptide hormones. Primary sequences analysis have led to the finding of seven segments of eighteen or more relatively hydrophobic residues that are believed to represent transmembrane helices that take part in creating an intramembranous helical bundle <ref name="Lastt">PMID: 26227798</ref>. Also, mutagenesis has been used to determine which residues were necessary in maximizing affinity for glucagon, mutagenesis being the process of mutating certain residues and observing the effect on affinity. If a residue held little importance to the overall affinity, the mutation would show little change in affinity. Finally, the orientation and mechanism of the peptide interactions within these structures are studied using peptide structure-activity relationships (SAR), receptor and ligand fragments, chimeric receptors, site-directed mutagenesis, photochemical cross-linking, and molecular modeling <ref name="Lastt">PMID: 26227798</ref>.
 </StructureSection>
-==Clinical Relevancy==
-Of the fifteen human class B GPCRs, eight have been identified as potential [https://en.wikipedia.org/wiki/Biological_target drug target]<ref name="Drug">PMID: 24628305</ref>. [http://www.wisegeek.com/what-are-therapeutic-agents.htm Therapeutic agents] have been created from the peptides themselves within this protein, but overall [https://en.wikipedia.org/wiki/Pharmaceutical_industry pharmaceutical companies] have had difficulty creating agents that act on family B GPCRS. There is an outward appearance and inherent flexibility in the class B GCGR 7TM because of conserved hydrogen bonds that flank a [https://en.wikipedia.org/wiki/Glycine glycine] residue, and this structure along with the ECD and its role of interactions on the extracellular side of receptors may provide evidence to how class B receptors adjust its conformational spectra for various receptors. Researchers hope to show how these conformations can be utilized in potential treatments of a wide array [https://en.wikipedia.org/wiki/List_of_mental_disorders disorders]. Research for class B GCGR [https://en.wikipedia.org/wiki/Enzyme_inhibitor inhibitors] is primarily looking into [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric inhibitors] having the ability to target specific receptors in order to treat problems like stress disorders, managing excess glucose in the bloodstream, and also alternative mechanisms for treating [https://en.wikipedia.org/wiki/Migraine migraines] <ref name="Inhibitors">PMID: 24189067</ref>. Known inhibitors include [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibodies] which inhibit GCGR through an allosteric mechanism. The monoclonal antibodies bind to two different sites, the ECD opposite of the binding region and then the helical portion of the ECD as well. These antibodies did not interact with the binding sites, but overall this inhibitor shows further proof that the ECD is extremely important for proper functioning of  human class B GCGRs <ref name="Last">PMID: 19305799</ref>. Determining the structure of class B GCGRs is a reason for its lack of advanced knowledge in the field, but X-ray crystallography and NMR have been the main processes performed and have had some success with it over the past couple years <ref name="Lastt">PMID: 26227798</ref>. X-ray crystallography displayed the crystal structure of ECDs of class B GPCRs in complex with their ligands along with the crystal structure of the 7TM. In addition to this, NMR has allowed the ability to directly understand structures of soluble amino-terminal domains of numerous members of the secretin-like family that bind peptide hormones. Primary sequences analysis have led to the finding of seven segments of eighteen or more relatively hydrophobic residues that are believed to represent transmembrane helices that take part in creating an intramembranous helical bundle <ref name="Lastt">PMID: 26227798</ref>. Also, mutagenesis has been used to determine which residues were necessary in maximizing affinity for glucagon, mutagenesis being the process of mutating certain residues and observing the effect on affinity. If a residue held little importance to the overall affinity, the mutation would show little change in affinity. Finally, the orientation and mechanism of the peptide interactions within these structures are studied using peptide structure-activity relationships (SAR), receptor and ligand fragments, chimeric receptors, site-directed mutagenesis, photochemical cross-linking, and molecular modeling <ref name="Lastt">PMID: 26227798</ref>.