Sandbox 121: Difference between revisions
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The Beta-2 Adrenergic Receptor (B₂AR) is a G-protein coupled receptor (GPCR) which, when stimulated by a catecholamine, causes the relaxation of various smooth muscles, and the production of glucose by glycogenolysis and gluconeogenesis. Pharmaceuticals acting through B2AR are important for treating asthma, chronic obstructive pulmonary disease (COPD), and premature labor. The structure of B2AR consists of 7-transmembrane domains, connected by three extracellular loops and three intracellular loops. At the base of the extracellular loops, buried within the transmembrane helices, there is a predominately hydrophobic binding pocket with several crucial polar residues that interact with ligands. Interestingly, certain polar interactions appear to play a role in the conversion of the receptor from an active to an inactive state. Recent crystallography of B2AR has revealed that the active state, relative to the inactive state, shows only minor changes in the binding pocket, whereas critical shifts occur at the cytoplasmic face. These conformational changes lead to a dissociation of the G-protein from the receptor, which then initiates a signaling cascade. The Hostos-Lincoln Academy SMART team (Students Modeling A Research Topic) modeled ligands in complex with B2AR using 3D printing technology. Supported by grants from the HHMI Precollege Program and the Camille and Henry Dreyfus Foundation. | The Beta-2 Adrenergic Receptor (B₂AR) is a G-protein coupled receptor (GPCR) which, when stimulated by a catecholamine, causes the relaxation of various smooth muscles, and the production of glucose by glycogenolysis and gluconeogenesis. Pharmaceuticals acting through B2AR are important for treating asthma, chronic obstructive pulmonary disease (COPD), and premature labor. The structure of B2AR consists of 7-transmembrane domains, connected by three extracellular loops and three intracellular loops. At the base of the extracellular loops, buried within the transmembrane helices, there is a predominately hydrophobic binding pocket with several crucial polar residues that interact with ligands. Interestingly, certain polar interactions appear to play a role in the conversion of the receptor from an active to an inactive state. Recent crystallography of B2AR has revealed that the active state, relative to the inactive state, shows only minor changes in the binding pocket, whereas critical shifts occur at the cytoplasmic face. These conformational changes lead to a dissociation of the G-protein from the receptor, which then initiates a signaling cascade. The Hostos-Lincoln Academy SMART team (Students Modeling A Research Topic) modeled ligands in complex with B2AR using 3D printing technology. Supported by grants from the HHMI Precollege Program and the Camille and Henry Dreyfus Foundation. | ||
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==='''Background Information'''=== | ==='''Background Information'''=== | ||
{| | {|align='right' | ||
|[[Image:B2AR-Adernergic synapse.JPG | |[[Image:B2AR-Adernergic synapse.JPG|thumb|alt= Alt text| Adernergic Synapse |400px]] | ||
|[[Image:B2AR-Norepinephrine.JPG | |[[Image:B2AR-Norepinephrine.JPG|thumb|alt= Alt text| Norephrine |300px]] | ||
|} | |} | ||
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<applet load='3P0G' size='300' frame='true' align='right' scene='Sandbox_121/B2ar_struc/1' caption='B₂AR Active'/> | <applet load='3P0G' size='300' frame='true' align='right' scene='Sandbox_121/B2ar_struc/1' caption='B₂AR Active'/> | ||
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==='''Conformational Change'''=== | ==='''Conformational Change'''=== | ||
[[Image:B2AR-Binding_Pocket_OH.JPG|thumb|left|alt= Alt text| Models of isoproternol binding to two B2AR structures. (a) Inactive B2AR: 4.78Å distance between the catechol-OH of the ligand and Ser207 of TM5 is too large for a H-bond. (b) Active B2AR: A hydrogen bond distance of 2.17Å between the catechol-OH of the ligand and Ser207 on TM5 is shown. |300px]] | [[Image:B2AR-Binding_Pocket_OH.JPG|thumb|left|alt= Alt text| Models of isoproternol binding to two B2AR structures. (a) Inactive B2AR: 4.78Å distance between the catechol-OH of the ligand and Ser207 of TM5 is too large for a H-bond. (b) Active B2AR: A hydrogen bond distance of 2.17Å between the catechol-OH of the ligand and Ser207 on TM5 is shown. |300px]] | ||
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==='''Molecular Morph'''=== | ==='''Molecular Morph'''=== | ||
The coordinates for molecular morphs between inactive state of B2AR (2rh1) and active state (3p0g) were generated using iPyMOL and eMovie (http://www.weizmann.ac.il/ISPC/eMovie.html). Morphs, a series of 10 linear interpolations between a starting and finishing model, are useful when viewing the transition of a conformational change. This model of B2AR using morphs should not be thought of as precise animation of conformational changes upon activation but rather as a comparison of the inactive state to the active state. | The coordinates for molecular morphs between inactive state of B2AR (2rh1) and active state (3p0g) were generated using iPyMOL and eMovie (http://www.weizmann.ac.il/ISPC/eMovie.html). Morphs, a series of 10 linear interpolations between a starting and finishing model, are useful when viewing the transition of a conformational change. This model of B2AR using morphs should not be thought of as precise animation of conformational changes upon activation but rather as a comparison of the inactive state to the active state. | ||
