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Structural features of ?2 adrenergic receptor: crystal structures and beyond.

ABSTRACT: The beta2-adrenergic receptor (?2AR) family, which is the largest family of cell surface receptors in humans. Extra attention has been focused on the human GPCRs because they have been studied as important protein targets for pharmaceutical drug development. In fact, approximately 40% of marketed drugs directly work on GPCRs. GPCRs respond to various extracellular stimuli, such as sensory signals, neurotransmitters, chemokines, and hormones, to induce structural changes at the cytoplasmic surface, activating downstream signaling pathways, primarily through interactions with heterotrimeric G proteins or through G-protein independent pathways, such as arrestin. Most GPCRs, except for rhodhopsin, which contains covalently linked 11 cis-retinal, bind to diffusible ligands, having various conformational states between inactive and active structures. The first human GPCR structure was determined using an inverse agonist bound ?2AR in 2007 and since then, more than 20 distinct GPCR structures have been solved. However, most GPCR structures were solved as inactive forms, and an agonist bound fully active structure is still hard to obtain. In a structural point of view, ?2AR is relatively well studied since its fully active structure as a complex with G protein as well as several inactive structures are available. The structural comparison of inactive and active states gives an important clue in understanding the activation mechanism of ?2AR. In this review, structural features of inactive and active states of ?2AR, the interaction of ?2AR with heterotrimeric G protein, and the comparison with ?1AR will be discussed.

SUBMITTER: Bang I

PROVIDER: S-EPMC4332033 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Structural features of β2 adrenergic receptor: crystal structures and beyond.

Bang Injin I Choi Hee-Jung HJ

Molecules and cells 20141224 2

The beta2-adrenergic receptor (β2AR) family, which is the largest family of cell surface receptors in humans. Extra attention has been focused on the human GPCRs because they have been studied as important protein targets for pharmaceutical drug development. In fact, approximately 40% of marketed drugs directly work on GPCRs. GPCRs respond to various extracellular stimuli, such as sensory signals, neurotransmitters, chemokines, and hormones, to induce structural changes at the cytoplasmic surfac ...[more]

PMID: 25537861

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Project description:PurposeG protein-coupled receptors (GPCRs) are a superfamily of membrane proteins of vast pharmaceutical interest. Here, we describe a graph theory-based analysis of the structure of the β2 adrenergic receptor (β2 AR), a prototypical GPCR. In particular, we illustrate the network of direct and indirect interactions that link each amino acid residue to any other residue of the receptor.MethodsNetworks of interconnected amino acid residues in proteins are analogous to social networks of interconnected people. Hence, they can be studied through the same analysis tools typically employed to analyze social networks - or networks in general - to reveal patterns of connectivity, influential members, and dynamicity. We focused on the analysis of closeness-centrality, which is a measure of the overall connectivity distance of the member of a network to all other members.ResultsThe residues endowed with the highest closeness-centrality are located in the middle of the seven transmembrane domains (TMs). In particular, they are mostly located in the middle of TM2, TM3, TM6 or TM7, while fewer of them are located in the middle of TM1, TM4 or TM5. At the cytosolic end of TM6, the centrality detected for the active structure is markedly lower than that detected for the corresponding residues in the inactive structures. Moreover, several residues acquire centrality when the structures are analyzed in the presence of ligands. Strikingly, there is little overlap between the residues that acquire centrality in the presence of the ligand in the blocker-bound structures and the agonist-bound structures.ConclusionsOur results reflect the fact that the receptor resembles a bow tie, with a rather tight knot of closely interconnected residues and two ends that fan out in two opposite directions: one toward the extracellular space, which hosts the ligand binding cavity, and one toward the cytosol, which hosts the G protein binding cavity. Moreover, they underscore how interaction network is by the conformational rearrangements concomitant with the activation of the receptor and by the presence of agonists or blockers.

Project description:The gene encoding the β2-adrenergic receptor (β2-AR) is polymorphic, which results in possible differences in a primary structure of this protein. It has been shown that certain types of polymorphisms are correlated with some clinical features of asthma, including airways reactivity, whereas the influence of other is not yet understood. Among polymorphisms affecting amino acids at positions 16, 27, 34, 164 and 220, the latter three are present in the crystal structure of β2-AR, which facilitates studying them by means of molecular dynamics simulations. The current study was focused on investigating to what extent the three polymorphisms of β2-AR (i.e., Val34Met, Thr164Ile and Ser220Cys) affect the interaction of β2-AR with its natural molecular environment which includes: lipid bilayer (in the case of all three polymorphs) and Gs protein (which participates in β2-AR-mediated signaling; in the case of Ser220Cys). We have designed and carried out a series of molecular dynamics simulations at different level of resolution (i.e., either coarse-grained or atomistic simulations), accompanied by thermodynamic integration protocol, in order to identify potential polymorphism-induced alterations in structural, conformational or energetic features of β2-AR. The results indicate the lack of significant differences in the case of energies involved in the β2-AR-lipid bilayer interactions. Some differences have been observed when considering the polymorphism-induced alterations in β2-AR-Gs protein binding, but their magnitude is also negligible in relation to the absolute free energy difference correlated with the β2-AR-Gs affinity. The Val34Met and Thr164Ile polymorphisms are weakly correlated with alteration of the conformational features of the receptor around polymorphic sites. On the contrary, it has been concluded that the Ser220Cys polymorphism is correlated with several structural alterations located in the intracellular region of β2-AR, which can induce G-protein binding and, subsequently, the polymorphism-correlated therapeutic responses. More precisely, these alterations involve vicinity of intracellular loops and, in part, are the direct consequence of disturbed interactions of Ser/Cys220 sidechain within 5th transmembrane domain. Structurally, the dynamic structure exhibited by the β2-ARSer220 polymorph is closer to the Gs-compatible structure of β2-AR.

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Structural features of ?2 adrenergic receptor: crystal structures and beyond.

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Structural features of β2 adrenergic receptor: crystal structures and beyond.

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