4QKX

Structure of beta2 adrenoceptor bound to a covalent agonist and an engineered nanobody

Summary for 4QKX

• Entry DOI: 10.2210/pdb4qkx/pdb
• Descriptor: Beta-2 adrenergic receptor, R9 protein, SODIUM ION, ... (4 entities in total)
• Functional Keywords: 7-transmembrane helices, signal transduction, g proteins, membrane, membrane protein-immune system complex, membrane protein/immune system
• Biological source: Enterobacteria phage T4; More
• Cellular location: Cell membrane ; Multi- pass membrane protein : P07550
• Total number of polymer chains: 2
• Total formula weight: 66810.86

Authors

Weichert, D.,Kruse, A.C.,Manglik, A.,Hiller, C.,Zhang, C.,Huebner, H.,Kobilka, B.K.,Gmeiner, P. (deposition date: 2014-06-10, release date: 2014-07-23, Last modification date: 2024-11-20)

Primary citation

Weichert, D.,Kruse, A.C.,Manglik, A.,Hiller, C.,Zhang, C.,Hubner, H.,Kobilka, B.K.,Gmeiner, P.
Covalent agonists for studying G protein-coupled receptor activation.
Proc.Natl.Acad.Sci.USA, 111:10744-10748, 2014

PubMed Abstract: Structural studies on G protein-coupled receptors (GPCRs) provide important insights into the architecture and function of these important drug targets. However, the crystallization of GPCRs in active states is particularly challenging, requiring the formation of stable and conformationally homogeneous ligand-receptor complexes. Native hormones, neurotransmitters, and synthetic agonists that bind with low affinity are ineffective at stabilizing an active state for crystallogenesis. To promote structural studies on the pharmacologically highly relevant class of aminergic GPCRs, we here present the development of covalently binding molecular tools activating Gs-, Gi-, and Gq-coupled receptors. The covalent agonists are derived from the monoamine neurotransmitters noradrenaline, dopamine, serotonin, and histamine, and they were accessed using a general and versatile synthetic strategy. We demonstrate that the tool compounds presented herein display an efficient covalent binding mode and that the respective covalent ligand-receptor complexes activate G proteins comparable to the natural neurotransmitters. A crystal structure of the β2-adrenoreceptor in complex with a covalent noradrenaline analog and a conformationally selective antibody (nanobody) verified that these agonists can be used to facilitate crystallogenesis.

PubMed: 25006259
DOI: 10.1073/pnas.1410415111

Experimental method

X-RAY DIFFRACTION (3.3 Å)