Related Experiment Video
Updated: Jul 24, 2025
09:30
Author Spotlight: Exploring Cellular Processes by Modeling Ligands in Cryo-EM Maps
Published on: July 19, 2024
1.4K
Distinct Conformations of Mirabegron Determined by MicroED
Jieye Lin1, Johan Unge1, Tamir Gonen1,2,3
1Department of Biological Chemistry, University of California, Los Angeles, 615 Charles E. Young Drive South, Los Angeles, California 90095, United States.
Biorxiv : the Preprint Server for Biology
|July 10, 2023
Summary
Mirabegron, a medication for overactive bladder, reveals its 3D structure and two distinct forms using MicroED. The drug undergoes significant conformational changes when binding to its target receptor.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Mirabegron (Myrbetriq) is a widely prescribed medication for overactive bladder syndrome.
- The three-dimensional structure and conformational behavior of Mirabegron upon receptor binding were previously unknown.
Approach:
- Microcrystal electron diffraction (MicroED) was utilized to determine the 3D structure of Mirabegron.
- The study analyzed hydrogen bonding and crystal packing to understand the drug's properties.
Key Points:
- Mirabegron was found to exist in two distinct conformational states (trans- and cis-forms).
- The drug exhibits hydrophilic groups embedded in the crystal lattice, leading to a hydrophobic surface and low water solubility.
- Structural comparison indicates significant conformational changes upon binding to the beta 3 adrenergic receptor (β3AR).
Conclusions:
- MicroED is effective for determining the structures of active pharmaceutical ingredients (APIs), including polymorphic forms.
- Understanding Mirabegron's structure and conformational flexibility provides insights into its mechanism of action at the β3AR.
More Related Videos
Related Concept Videos
02:20Conformations of Butane
14.4K
Unlike ethane and propane that have only two major conformations, butane has more than two conformers. The staggered form of butane in which the bulky methyl groups on the two carbons are placed on opposite sides, that is, at a dihedral angle of 180°, is the lowest energy, most stable form — called the anti conformer. This conformation is stabilized due to the absence of steric repulsion between the largely spaced out methyl groups. The other two staggered conformations are...
14.4K
01:16Adrenergic Agonists: Chemistry and Structure-Activity Relationship
3.1K
Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of...
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of...
3.1K
01:23Drugs Affecting GI Tract Motility: Serotonin Receptor Agonists
313
Serotonin, a crucial neurotransmitter synthesized by enterochromaffin cells, plays a cardinal role in regulating gastrointestinal (GI) motility. With over 90% of the body's total serotonin in the GI tract, its influence on digestive processes is profound. Serotonin is swiftly released upon various stimuli, such as food boluses or certain drugs, triggering intrinsic sensory neurons in the myenteric plexus and extrinsic vagal and spinal sensory neurons. This leads to the activation of the...
313
01:24Cholinergic Antagonists: Pharmacokinetics
520
Cholinergic antagonists—such as antimuscarinics—are available in oral, topical, ocular, parenteral, and inhalational formulations. Most antimuscarinics are oral formulations, while scopolamine is available as a topical patch, and ipratropium and tiotropium are available as inhalation aerosols or powders. Atropine, tropicamide, and cyclopentolate are topically instilled in the eye. Most antimuscarinics are lipid-soluble and readily absorbed from the gastrointestinal tract and...
520
01:22Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
1.1K
Cholinergic agonists or cholinomimetics mimic the action of acetylcholine to stimulate the parasympathetic nervous system. They are categorized into direct-acting and indirect-acting agents. The direct-acting cholinergic drugs induce the parasympathetic response by directly binding to the muscarinic or nicotine receptors. In comparison, the indirect-acting cholinergic drugs prevent acetylcholine hydrolysis, indirectly contributing to the extended parasympathetic response.
The direct-acting...
The direct-acting...
1.1K
01:29Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
608
Indirect-acting cholinergic agonists are agents that interact with the acetylcholinesterase enzyme in the synaptic cleft, preventing the breakdown of acetylcholine into choline and acetate. Consequently, the concentration of acetylcholine in the synaptic cleft increases. These agonists can be classified into reversible and irreversible inhibitors based on their duration of action.
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
608