8w1v | pdb_00008w1v

The beta2 adrenergic receptor bound to a bitopic ligand

spinqualitylabelsall models 8w1v, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8w1v is a 4 chain structure with sequence from Homo sapiens and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3Å Ligands: A1AE2, AV0 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ADRB2_HUMAN Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. The beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine.ENLYS_BPT4 Endolysin with lysozyme activity that degrades host peptidoglycans and participates with the holin and spanin proteins in the sequential events which lead to the programmed host cell lysis releasing the mature viral particles. Once the holin has permeabilized the host cell membrane, the endolysin can reach the periplasm and break down the peptidoglycan layer. Publication Abstract from PubMed Metastable binding sites (MBS) have been observed in a multitude of molecular dynamics simulations and can be considered low affinity allosteric binding sites (ABS) that function as stepping stones as the ligand moves toward the orthosteric binding site (OBS). Herein, we show that MBS can be utilized as ABS in ligand design, resulting in ligands with improved binding kinetics. Four homobivalent bitopic ligands (1-4) were designed by molecular docking of (S)-alprenolol ((S)-ALP) in the cocrystal structure of the beta(2) adrenergic receptor (beta(2)AR) bound to the antagonist ALP. Ligand 4 displayed a potency and affinity similar to (S)-ALP, but with a >4-fold increase in residence time. The proposed binding mode was confirmed by X-ray crystallography of ligand 4 in complex with the beta(2)AR. This ligand design principle can find applications beyond the beta(2)AR and G protein-coupled receptors (GPCRs) as a general approach for improving the pharmacological profile of orthosteric ligands by targeting the OBS and an MBS simultaneously. Bitopic Ligands Support the Presence of a Metastable Binding Site at the beta(2) Adrenergic Receptor.,Gaiser BI, Danielsen M, Xu X, Ropke Jorgensen K, Fronik P, Marcher-Rorsted E, Wrobel TM, Liu X, Mosolff Mathiesen J, Sejer Pedersen D J Med Chem. 2024 Jul 11;67(13):11053-11068. doi: 10.1021/acs.jmedchem.4c00578. , Epub 2024 Jul 1. PMID:38952152 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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