The Human B2-adrenergic G protein-coupled receptor (PDB ID: 2RH1)
Created by Philip Snell
Description
The Human B2-Adrenergenic G-Protein coupled receptor(B2AR) is a member of the guanine nucleotide binding protein(G-Protein) coupled receptors (GPCRs). GPCRs represent the most common kind of cross-membrane signal transduction proteins. (1) GPCRs bind to receptors from outside the cells and start a signal transduction pathway within the cell. These GPCRs represent the largest family of eukaryotic signal transduction proteins. (4) B2AR falls within this category along with human rhodopsin, one of the most exhaustively studied GPCRs. Despite some similarities between these two proteins, there are distinct differences between their protein structures which causes markedly different functions within the cell.
Both are transmembrane proteins, but rhodopsin receives light in the eyes, while B2AR reacts with transmitters to regulate smooth muscle in the lungs, and throat. (3) Studying B2AR has shown practical benefits because some B2AR agonists are already used to treat asthma and preterm abortion. (4) By more effectively examining the possible structural determinants of ligand specificity, and antagonist bonding in B2AR, researchers could gain deeper insight into the treatment of heart or long problems, using beta-blockers.
Structure
Overall Structure:
This structural model was taken of the B2AR-protein bound to
T4-Lysozome in place of the third intracellular loop to induce crystallization. The B2-Adrenergenic G-Protein coupled receptor, (view
secondary structure,) is a monomer structured according to the typical transmembrane protein model of two domains, the hydrophilic core within the membrane and extracellular loops that react with diffusible ligands. Its transmembrane core consists of 7 transmembrance helices, typical of the GPCR's, and it also has three intra cellular loops and three extracellular loops.
The seven helices form the main binding site and core of the molecule. Helices II, V, VI, and VII have a proline induced kink. This kink is thought to enable G protein structure rearrangements that could activate the protein G protein, signaling one of the signal transduction pathways GPCRs catalyze(4). One of the most important functions of the helices is that extracellular portions of helices III, IV, V, and VII serve as the location for agonist bonding within the protein(1). (4) The antagonist used in this crystalization is corazalol. Corazalol enters the transmembrane portion of the molecule and enters the binding site. Three residues bind with the hydroxyl or amine portions of the ligand,
Tyr-316, Asp-113, and Asn-312. The bonds between Asp-113, Asn-312, and the ligand are especialy strong due to the hydrogen bonding(3). Asp-113 was recognized to be especially important after experiments demonstrated that mutations in residue 113 prevent any agonist binding(1). Along with these hydrophilic residues there are three hydrophic residues,
Val-114, Phe-290, and Phe-193 that interact with the hydrophobic portion of the ligand. The side chains of Phe-193, Phe-290, and Val-114 interact with the non-polar portion of corazalol to increase binding affinity. In combination these 5 residues surround and stabilize the ligand(View
full protein, and
individual residues in the the
binding pocket .
While it initially appears as a monomer recent analysis has suggested that B2AR may exist as a dimer in the plasma membrane, and that helix IV could act as the dimer interface under the correct conditions. (4)
Along with the transmembrane helices there are 3 Intracellular Loops (ICLs) and 3 Extracellular loops (ECLS). Of these ELC2 is one of the most important. ECL2 consists of residues 172-196, and features a short helical segment. The ECL2 loop also exposes more surface area to the solution than the other coils, which has to be stabilized by an interloop disulfide bond from Cys184-Cys190, and disulfide bond to the transmembrane core from Cys106- Cys191. (4) This disulfide bond to the core works with ECL2s short helical to restrict the movement the ECL2 loop and limit its conformations. (1) The restricted movement also prevents ECL2 from interfering with the transmembrane binding pocket, and gives water soluble ligands easy access to the core. (5)
There is also an interaction between receptors that is mediated primarily by lipids consisting of six cholesterol and two palmitic acid molecules, the latter being covalently attached to Cys-314(3). Within sample there are three cholesterols and one palmitic acid molecule bonded to the protein(1). Dodecethylene glycol, 1,4 Butane diol, and Maltose are also attached to the protein; however, it is likely that these compounds were necessary to crystallize the protein.
Biological Significance
B2AR proteins are transmembrane proteins primarily located within the smooth muscle of the pulmonary and cardial tissues specifically on cardiac myocytes vascular smooth muscle cells, and bronchial smooth muscle(2). This can be seen in its arrangement in the following
cell membrane diagram. B2AR serves as a part of the sympathetic nervous system by binding to diffusible hormones, adrenaline and noradrenaline.(3) Binding of B2AR with these neurotransmitters begins a signal transduction pathways which control heart and lung function, primarily changes in myocardial metabolism, systolic and diastolic pressures, and heart rate. (2)
Comparison To Other Proteins
The human A2A adenosine receptor(A2A), is a separate form of GPCR that responds to extracellular adenosine instead of amines(4). The E score of 8e-128 on the Protein Basic Local Alignment Search Tool (PBlast) indicates a remarkable similarity between the primary structure of A2A and B2AR. The proteins are also similar on a three dimensional level having a Z score (obtained from the Dali server) of 35.1, and a root mean squared deviation of 11.3 angstroms, the average distance between the backbones of the two superimposed proteins. The structural similarities are easily visible by
superimposition and by comparing the binding site of the B2AR protein with the
A2A protein These structural similarities lead to similar functions among these proteins. Both proteins are transmembrane GPCRs that transmit bind with hormones to transmit a message. However adenosine G-proteins serve to regulate pain, cerebral blood flow, basal ganglia functions, sleep, and respiration with the central nervous system(4). B2AR receives messages in the sympathetic nervous system, to regulate the pulmonary and cardial system(3). Both of the proteins bind with different hormones to cause signal cascades that cause a variety of functions.