5a8e

thermostabilised beta1-adrenoceptor with rationally designed inverse agonist 7-methylcyanopindolol bound

spinqualitylabelsall models 5a8e, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5a8e is a 1 chain structure with sequence from Melga. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: MHA, NA, OLC, XTK Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [ADRB1_MELGA] Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. This receptor binds epinephrine and norepinephrine with approximately equal affinity. Publication Abstract from PubMed Comparisons between structures of the lower case beta1-adrenergic receptor (beta1AR) bound to either agonists, partial agonists or weak partial agonists led to the proposal that rotamer changes of Ser5.46, coupled to a contraction of the binding pocket, are sufficient to increase the probability of receptor activation. Cyanopindolol is a weak partial agonist of beta1AR and, based on the hypothesis above, we predicted that the addition of a methyl group to form 7-methylcyanopindolol would reduce dramatically its efficacy. An eight-step synthesis of 7-methylcyanopindolol was developed and its pharmacology analysed. 7-Methylcyanopindolol bound with similar affinity to cyanopindolol to both beta1AR and beta2AR. As predicted, the efficacy of 7-methylcyanopindolol was dramatically reduced compared to cyanopindolol, acting as a very weak partial of turkey beta1AR and an inverse agonist of human beta2AR. The structure of 7-methylcyanopindolol-bound beta1AR was determined to 2.4 A resolution and found to be virtually identical to the structure of cyanopindolol-bound beta1AR. The major differences in the orthosteric binding pocket are that it has expanded by 0.3 A in 7-methylcyanopoindol-bound beta1AR and the hydroxyl group of Ser5.46 is positioned 0.8 A further from the ligand with respect to the position of the Ser5.46 side chain in cyanopindolol-bound beta1AR. Thus the molecular basis for the reduction in efficacy of 7-methylcyanopindolol compared to cyanopindolol may be regarded as the opposite of the mechanism proposed for the increase in efficacy of agonists compared to antagonists. Pharmacological Analysis and Structure Determination of 7-Methylcyanopindolol-Bound beta1-Adrenergic Receptor.,Sato T, Baker J, Warne T, Brown G, Leslie A, Congreve M, Tate C Mol Pharmacol. 2015 Sep 18. pii: mol.115.101030. PMID:26385885 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Adrenergic receptor 3D structures

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