CHISHIKI

Platform Technology

Expanding the scope of GPCR structure-based drug design with cryoEM

By Stacey Southall, Mathieu Rappas, Gabriella Cseke, Giancarlo Tria, Rob Cooke | Nov 15, 2019

About the Conference

27th Protein Structure Determination in Industry Meeting (PSDI) 2019

Organised by AstraZeneca

3-5 November 2019

Wellcome Conference Centre怀Hinxton, Cambridgeshire, UK

Conference Website

 

Summary          

Stacey Southall, Associate Director, Head of Biophysics, attended the 27th Protein Structure Determination in Industry Meeting (PSDI) 2019 organised by AstraZeneca in Cambridgeshire, UK on 4th November and presented on “Expanding the scope of GPCR structure-based drug design with cryoEM”.

 

Abstract

G protein-coupled receptors (GPCRs) continue to be an important family of drug targets. Despite many success stories, today there are still a significant number of GPCRs with compelling pre-clinical validation that remain highly challenging for drug discovery. Over the last 10 years there has been substantial progress in the structural biology of GPCRs facilitating Structure-Based Drug Design (SBDD) approaches. Sosei Heptares uses its proprietary StaR® technology to thermostabilise GPCRs to facilitate biophysical and structural studies.

Using the StaR® approach, Sosei Heptares has solved many high-resolution structures of GPCRs by X-ray crystallography, revealing the diversity in GPCR ligand binding sites. These structural insights have presented opportunities in rational drug design for GPCR targets at both orthosteric and allosteric binding sites.

At Sosei Heptares we have taken advantage of recent advances in the field of cryo-electron microscopy to incorporate single-particle analysis into our SBDD workflow. Here I describe why StaR® proteins are advantageous in generating optimised samples for GPCR structure determination by single-particle cryo-electron microscopy. I also reflect on the type of information that can presently be obtained by CryoEM of GPCRs, the challenges associated with obtaining them and comment on the future role of this technique in SBDD.

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