Sandbox 121

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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.