GPCR Structure Determination By Cryo-EM

Single Particle cryogenic electron microscopy (cryo-EM) is the latest revolution in structural biology, as the technological improvements now allow structure determination of low molecular weight samples (<200kDa) to near-atomic resolution. It has special advantages compared to X-ray crystallography for membrane protein complexes that are traditionally very challenging to crystallize. The technology is still rapidly evolving and has yet to be a mainstream choice for structure-based drug development.

ConfometRx is a pioneer in this field. ConfometRx has established in-house cryo-EM capability and successfully employed cryo-EM to solve a series of iterative structures of a GPCR-G protein complex bound to various candidate compounds (orthosteric and allosteric) from a pharmaceutical partner, reaching as high as 2.8Å resolution to allow confident identification of ligand binding mode and even water molecules. To our knowledge, this is the first case of a cryo-EM structure revealing the binding mode of compounds under active optimization in a drug discovery pipeline, at least for a GPCR target. This is also a proof-of-concept that cryo-EM technology can produce structures with sufficient resolution, quality and turnaround time to facilitate structure-based drug discovery and optimization, even for compounds with micromolar affinity. We will continue to optimize the technology to enable the determination of inactive-state structures by cryo-EM.

With the comprehensive expertise and experience in GPCR biochemistry, crystallography and cryo-EM, ConfometRx is able to provide service to determine novel or iterative structures of GPCRs in their physiologically and/or pharmacologically relevant states.