Beta-2 Adrenergic Receptor: Difference between revisions
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====Strucutre of B2ARs==== | ====Strucutre of B2ARs==== | ||
As a family, GPCRs are renowned for their structure solution difficulty. In this model, Beta2-Adrenergic Receptor (B2AR) – T4 Lysozyme fusion was developed to allow for structure solution. Fortunately, the <scene name='Beta-2_Adrenergic_Receptor/Opening_lyso/1'>lysozyme portion</scene> of the structure does not appear to impact the structure of the B2AR. The structure of B2AR is very similar to the GPCR [[Rhodopsin]], which is a photoreceptor in the retina which allows the perception of light. B2AR is a transmembrane protein with <scene name='Beta-2_Adrenergic_Receptor/Helices/1'>7 transmembrane helices</scene> and an 8th helix which runs parallel to the cytoplasmic face of the membrane.<ref name="Rasmussen">PMID: 17952055</ref> Helices 2,5,6 and 7 of B2AR have <scene name='Beta-2_Adrenergic_Receptor/Kinks/1'>kinks caused by prolines</scene> at conserved places, which are important for activation of G protein effectors. The extracellular regions on all GPCRs dictate the ligand specificity of GPCRs. The partial inverse agonist, Carazolol, binds to the receptor binding pocket of B2AR, reducing the basal activity of the receptor. This interaction involves residues Tyr 199, Ser 203, Ser 207, Phe 193, Ser 204, Ser 293, Phe 290, Tyr 308, Phe 289, Asn 312, Tyr 316, Trp 286, Trp 109 and Asp 113. Carazolol occupies a similar position as the rhodopsin inverse agonist, retinal. Carazolol does not act with the so called “toggle switch” on helix 6, but does interact with Phe 290, causing Trp 286 to assume an inactive rotameric state, effectively inhibiting B2AR activity.<ref>PMID: 17962520</ref> A conserved DRY motif (residues 129-131) is present in all GPCRs.<ref>PMID: 18547522</ref> In rhodopsin, the Arginine in this motif forms a salt bridge with a glutamate, an interaction that maintains rhodopsin in its inactive state until it is exposed to light. In B2AR, Arg 131 does not interact with Glu 268, which helps explain why B2AR has basal activity. Interestingly, Rhodopsin has no basil activity, a feature that is critical for vision.<ref>PMID: 18818650</ref> | As a family, GPCRs are renowned for their structure solution difficulty. In this model, Beta2-Adrenergic Receptor (B2AR) – T4 Lysozyme fusion was developed to allow for structure solution. Fortunately, the <scene name='Beta-2_Adrenergic_Receptor/Opening_lyso/1'>lysozyme portion</scene> of the structure does not appear to impact the structure of the B2AR. The structure of B2AR is very similar to the GPCR [[Rhodopsin]], which is a photoreceptor in the retina which allows the perception of light. B2AR is a transmembrane protein with <scene name='Beta-2_Adrenergic_Receptor/Helices/1'>7 transmembrane helices</scene> and an 8th helix which runs parallel to the cytoplasmic face of the membrane.<ref name="Rasmussen">PMID: 17952055</ref> Helices 2,5,6 and 7 of B2AR have <scene name='Beta-2_Adrenergic_Receptor/Kinks/1'>kinks caused by prolines</scene> at conserved places, which are important for activation of G protein effectors. The <scene name='Beta-2_Adrenergic_Receptor/Extracellular_residues/1'>extracellular regions</scene> on all GPCRs dictate the ligand specificity of GPCRs. The partial inverse agonist, Carazolol, binds to the receptor binding pocket of B2AR, reducing the basal activity of the receptor. This interaction involves residues Tyr 199, Ser 203, Ser 207, Phe 193, Ser 204, Ser 293, Phe 290, Tyr 308, Phe 289, Asn 312, Tyr 316, Trp 286, Trp 109 and Asp 113. Carazolol occupies a similar position as the rhodopsin inverse agonist, retinal. Carazolol does not act with the so called “toggle switch” on helix 6, but does interact with Phe 290, causing Trp 286 to assume an inactive rotameric state, effectively inhibiting B2AR activity.<ref>PMID: 17962520</ref> A conserved DRY motif (residues 129-131) is present in all GPCRs.<ref>PMID: 18547522</ref> In rhodopsin, the Arginine in this motif forms a salt bridge with a glutamate, an interaction that maintains rhodopsin in its inactive state until it is exposed to light. In B2AR, Arg 131 does not interact with Glu 268, which helps explain why B2AR has basal activity. Interestingly, Rhodopsin has no basil activity, a feature that is critical for vision.<ref>PMID: 18818650</ref> | ||
====Pharmaceutical Implications==== | ====Pharmaceutical Implications==== | ||