Sandbox 121
From Proteopedia
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Following binding of NE, to either alpha or beta receptors, conformational changes in the receptor lead to a disassociation of the G protein from the cytoplasmic face of the receptor which activates a second messenger, initiating a signaling cascade. | Following binding of NE, to either alpha or beta receptors, conformational changes in the receptor lead to a disassociation of the G protein from the cytoplasmic face of the receptor which activates a second messenger, initiating a signaling cascade. | ||
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| + | ==='''Beta 2 Adrenergic Receptor'''=== | ||
| + | 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. | ||
| + | B2AR is a single chain that crosses the lipid membrane 7 times from the extracellular to cytoplasmic surface. 3 extracellular loops and 3 intracellular loops are formed as the 7 transmembrane helices (TM1 to TM7) pass back and forth through the membrane. The binding pocket is located to the center of the extracellular surface | ||
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| + | ==='''Conformational Change'''=== | ||
| + | When an agonist is in the binding pocket a 2.1Å inward movement of TM5 at Ser207 is observed. This bulge at ser207 allows for a hydrogen bond between the ligand and the receptor. This interaction appears to be a key event in activation. | ||
| + | After the agonist binds, there is a rearrangement of interactions between residues located beneath the binding pocket that contributes to a rotation and outward movement of TM6 at Phe282. This change is associated with the breaking of the ionic lock between Glu268 in TM6 and Arg131 in TM3, resulting in an 11.4Å outward movement of the helix at the cytoplasmic face. | ||
| + | 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 | ||
Revision as of 18:59, 26 May 2011
Contents |
Physical Models of Beta 2 Adrenergic Receptor in its Inactive and Active States
Students: Mary Acheampong, Kavita Bhikhi, Daviana Dueno, Bobby Glover, Lachoy Harris, Alafia Henry, Randol Mata, and Marisa Vanbrakle, Hostos-Lincoln Academy of Science
Teacher: Allison Granberry, Hostos-Lincoln Academy of Science
Mentors: Haregewein Assefa,Touro College of Pharmacy, Thijs Beuming, Schrodinger
Introduction
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.
Background Information
Adrenergic receptors are involved in activation of the sympathetic nervous system following sudden external stimuli.
After arrival of a nerve impulse, the neurotransmitter norepinephrine (NE) is released from the presynaptic terminal of the sympathetic neuron. NE is a tyrosine derived catecholamine containing an amino-hydroxyethyl and a catechol group.
NE binds to adrenergic receptors embedded in the postsynaptic effector cell membrane.
Following binding of NE, to either alpha or beta receptors, conformational changes in the receptor lead to a disassociation of the G protein from the cytoplasmic face of the receptor which activates a second messenger, initiating a signaling cascade.
Beta 2 Adrenergic Receptor
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. B2AR is a single chain that crosses the lipid membrane 7 times from the extracellular to cytoplasmic surface. 3 extracellular loops and 3 intracellular loops are formed as the 7 transmembrane helices (TM1 to TM7) pass back and forth through the membrane. The binding pocket is located to the center of the extracellular surface
Conformational Change
When an agonist is in the binding pocket a 2.1Å inward movement of TM5 at Ser207 is observed. This bulge at ser207 allows for a hydrogen bond between the ligand and the receptor. This interaction appears to be a key event in activation. After the agonist binds, there is a rearrangement of interactions between residues located beneath the binding pocket that contributes to a rotation and outward movement of TM6 at Phe282. This change is associated with the breaking of the ionic lock between Glu268 in TM6 and Arg131 in TM3, resulting in an 11.4Å outward movement of the helix at the cytoplasmic face. 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
