Using MicroED for molecule conformations
This publication highlight is part of the SBGrid/Meharry Medical College Communities Project, focused on science education and demonstrating how structural biology and preclinical science connect to medicine.
Microcrystal electron diffraction (MicroED) is an emerging technique that has been shown to determine the solid-state structure of small molecules and small proteins in microcrystals. The ability to gain structural insight from microcrystals allows for a lower burden on crystallographers and opens a new range of target molecules that were previously unavailable due to their inability to form high-quality crystals. One such molecule is the commonly prescribed drug Mirabegron. Mirabegron is used to treat overactive bladder symptoms, yet a high quality structure of the molecule has eluded scientists due to its powdery crystalline state. SBGrid member Dr. Tamir Gonen, from UCLA, was able to determine a structure of Mirabegron using MicroED and sample a stable conformer state of this important drug.
Pictured above is Dog beta3 adrenergic receptor (grey) and Mirabegron (cyan). Mirabegron is shown deeply embedded in the binding site of this adrenergic receptor. PDB:7DH5. CC BY SBGRID
In a study published last month in Advanced Science, Prof. Gonen was able to show that Mirabegron has two distinct conformer states, a cis and trans, in a low energy crystal. This lattice unit is held together using a myriad of interactions between Mirabegron molecules, but a majority of the attraction is due to the demand to bury hydrophobic regions. While this arrangement is low energy and highly stable, it does not appear to be the conformer state found upon binding to target sites in proteins. The image above shows that Mirabegron buries deep into binding sites on proteins, and to do this it would need to go through a large conformational change from the states sampled in MicroED. These insights help to push forward our knowledge of the Mirabegron mechanism of action and could help describe the off-target effects of this drug.
- Vida Storm Robertson, Fisk University
Vida Storm Robertson is a Masters Student in Chemistry at Fisk University working in both solid-state and solution based structural determination techniques. He plans on starting a PhD program in biophysics next fall.
