INTRODUCTION:
UCLA researchers in the Department of Physiology have proposed a new and powerful method for unbiased structure based high throughput drug discovery for G-protein coupled receptors (GPCRs) using microcrystal electron diffraction (MicroED).
BACKGROUND:
X-ray crystallography is one of the techniques for determining protein structures at atomic resolution. However, application of this technique relies on the growth of large and well-ordered protein crystals necessary for X-ray diffraction experiments. Instead of X-rays, microcrystal electron diffraction (MicroED) uses electrons, which interact with matter more strongly than X-rays, allowing multiple scattering events to occur without dynamical scattering artifacts. Continuous rotation of the sample allows integration of the recorded electron reflections over the rocking curve, which leads to accurate structural data collection from nano-sized (~50 nm) crystals that are a billion times smaller than what is necessary for conventional crystallography. Thus, MicroED allows structure determination by electron diffraction from single crystals that are only ~1000 diffraction units, using an electron cryo-microscope (cryoEM).
INNOVATION:
Researchers at UCLA have proposed a G-protein coupled receptors (GPCRs)-targeted, structure-based high throughput drug screening method using MicroED. Nano-sized GPCR crystals allow efficient and homogenous diffusion of small molecules into the nanocrystal, leading to increased active site occupancy and improved electron density maps for high quality atomic structure-based drug screening.
POTENTIAL APPLICATIONS:
• High throughput drug screening
ADVANTAGES:
• GPCRs readily form nano crystals
• Nano crystals allows efficient diffusion of small molecules, leading to higher occupancy in the GPCR active site, higher quality electron density maps, and higher resolution structural data