5A8E

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

Summary for 5A8E

• Entry DOI: 10.2210/pdb5a8e/pdb
• Descriptor: BETA1 ADRENERGIC RECEPTOR, SODIUM ION, 4-[(2S)-3-(tert-butylamino)-2-hydroxypropoxy]-7-methyl-1H-indole-2-carbonitrile, ... (6 entities in total)
• Functional Keywords: signaling protein, inverse agonist
• Biological source: MELEAGRIS GALLOPAVO (TURKEY)
• Total number of polymer chains: 1
• Total formula weight: 38254.05

Authors

Sato, T.,Baker, J.G.,Warne, T.,Brown, G.A.,Congreve, M.,Leslie, A.G.W.,Tate, C.G. (deposition date: 2015-07-15, release date: 2015-09-30, Last modification date: 2024-10-23)

Primary citation

Sato, T.,Baker, J.,Warne, T.,Brown, G.,Leslie, A.,Congreve, M.,Tate, C.
Pharmacological Analysis and Structure Determination of 7-Methylcyanopindolol-Bound Beta1-Adrenergic Receptor.
Mol.Pharmacol., 88:1024-, 2015

PubMed Abstract: Comparisons between structures of the β1-adrenergic receptor (AR) bound to either agonists, partial agonists, or weak partial agonists led to the proposal that rotamer changes of Ser(5.46), coupled to a contraction of the binding pocket, are sufficient to increase the probability of receptor activation. (RS)-4-[3-(tert-butylamino)-2-hydroxypropoxy]-1H-indole-2-carbonitrile (cyanopindolol) is a weak partial agonist of β1AR and, based on the hypothesis above, we predicted that the addition of a methyl group to form 4-[(2S)-3-(tert-butylamino)-2-hydroxypropoxy]-7-methyl-1H-indole-2-carbonitrile (7-methylcyanopindolol) would dramatically reduce its efficacy. An eight-step synthesis of 7-methylcyanopindolol was developed and its pharmacology was analyzed. 7-Methylcyanopindolol bound with similar affinity to cyanopindolol to both β1AR and β2AR. As predicted, the efficacy of 7-methylcyanopindolol was reduced significantly compared with cyanopindolol, acting as a very weak partial agonist of turkey β1AR and an inverse agonist of human β2AR. The structure of 7-methylcyanopindolol-bound β1AR was determined to 2.4-Å resolution and found to be virtually identical to the structure of cyanopindolol-bound β1AR. The major differences in the orthosteric binding pocket are that it has expanded by 0.3 Å in 7-methylcyanopindolol-bound β1AR and the hydroxyl group of Ser(5.46) is positioned 0.8 Å further from the ligand, with respect to the position of the Ser(5.46) side chain in cyanopindolol-bound β1AR. Thus, the molecular basis for the reduction in efficacy of 7-methylcyanopindolol compared with cyanopindolol may be regarded as the opposite of the mechanism proposed for the increase in efficacy of agonists compared with antagonists.

PubMed: 26385885
DOI: 10.1124/MOL.115.101030

Experimental method

X-RAY DIFFRACTION (2.4 Å)