5X7D

Structure of beta2 adrenoceptor bound to carazolol and an intracellular allosteric antagonist

Summary for 5X7D

• Entry DOI: 10.2210/pdb5x7d/pdb
• Descriptor: Chimera protein of Beta-2 adrenergic receptor and Lysozyme, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, CHOLESTEROL, ... (8 entities in total)
• Functional Keywords: gpcr, signaling protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane ; Multi- pass membrane protein : P07550
• Total number of polymer chains: 1
• Total formula weight: 58946.53

Authors

Liu, X.,Ahn, S.,Kahsai, A.W.,Meng, K.-C.,Latorraca, N.R.,Pani, B.,Venkatakrishnan, A.J.,Masoudi, A.,Weis, W.I.,Dror, R.O.,Chen, X.,Lefkowitz, R.J.,Kobilka, B.K. (deposition date: 2017-02-25, release date: 2017-08-16, Last modification date: 2024-11-06)

Primary citation

Liu, X.,Ahn, S.,Kahsai, A.W.,Meng, K.C.,Latorraca, N.R.,Pani, B.,Venkatakrishnan, A.J.,Masoudi, A.,Weis, W.I.,Dror, R.O.,Chen, X.,Lefkowitz, R.J.,Kobilka, B.K.
Mechanism of intracellular allosteric beta 2AR antagonist revealed by X-ray crystal structure.
Nature, 548:480-484, 2017

PubMed Abstract: G-protein-coupled receptors (GPCRs) pose challenges for drug discovery efforts because of the high degree of structural homology in the orthosteric pocket, particularly for GPCRs within a single subfamily, such as the nine adrenergic receptors. Allosteric ligands may bind to less-conserved regions of these receptors and therefore are more likely to be selective. Unlike orthosteric ligands, which tonically activate or inhibit signalling, allosteric ligands modulate physiologic responses to hormones and neurotransmitters, and may therefore have fewer adverse effects. The majority of GPCR crystal structures published to date were obtained with receptors bound to orthosteric antagonists, and only a few structures bound to allosteric ligands have been reported. Compound 15 (Cmpd-15) is an allosteric modulator of the β adrenergic receptor (βAR) that was recently isolated from a DNA-encoded small-molecule library. Orthosteric β-adrenergic receptor antagonists, known as beta-blockers, are amongst the most prescribed drugs in the world and Cmpd-15 is the first allosteric beta-blocker. Cmpd-15 exhibits negative cooperativity with agonists and positive cooperativity with inverse agonists. Here we present the structure of the βAR bound to a polyethylene glycol-carboxylic acid derivative (Cmpd-15PA) of this modulator. Cmpd-15PA binds to a pocket formed primarily by the cytoplasmic ends of transmembrane segments 1, 2, 6 and 7 as well as intracellular loop 1 and helix 8. A comparison of this structure with inactive- and active-state structures of the βAR reveals the mechanism by which Cmpd-15 modulates agonist binding affinity and signalling.

PubMed: 28813418
DOI: 10.1038/nature23652

Experimental method

X-RAY DIFFRACTION (2.703 Å)