Sandbox 121: Difference between revisions

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

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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.

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.

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B2AR is a single chain that crosses the lipid membrane 7 times from the extracellular to cytoplasmic surface.  

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! scope="col" width="250" | Photo

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| BI-167107 || The active state of β₂AR was crystallized using BI-1671071 . Although it is not a catecholamine, it is a full agonist. || [[Image:B2AR-BI-167107-Structure.JPG|thumb|center|alt= Alt text| |300px]] || [[Image:B2AR-BI-167107-Picture.JPG|thumb|center|alt= Alt text| |250px]]

Notable differences between carazolol and both isoproterenol and the natural agonist norepinephrine are that:  

(i) Carazolol lacks the hydroxyl groups thought to be necessary for the activation of β₂AR.  

These are common characteristics of β₂AR antagonists.  

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==='''Ligand Binding'''===

Ligands share several key interactions in the binding pocket including:

in ECL2, Phe289 in TM6, and Phe290 inTM6.  

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==='''Conformational Change'''===

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==='''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.