Innovative technology enables first crystal structure of a class C GPCR drug target (mGlu5) transmembrane domain to be determined

Melbourn, UK, 17^th July 2014. The first high-resolution X-ray crystal structure of the metabotropic glutamate receptor 5 (mGlu₅) transmembrane domain was reported in Nature this week. The work was performed at Heptares Therapeutics, a leading drug discovery and development company using TTP Labtech’s innovative liquid handling technology for lipidic cubic phase crystallography (mosquito LCP).

Dr Andy Doré, Head of Crystallography at Heptares Therapeutics and joint first author of the recent article in Nature, stated, “the mosquito LCP was used for all crystallization setups of the mGlu₅-StaR resulting in us obtaining high resolution diffraction quality crystals for this receptor. The ability to reliably dispense low volume boli in 96 well LCP experiments using mosquito LCP is ideal for screening initial conditions and optimizing this and other difficult targets.”

mGlu₅ is a member of the GPCR family of proteins and plays an essential part in neuronal signaling making it an important drug target for modulating cell function and influencing neuropsychiatric disorders. Metabotropic glutamate receptors are Class C GPCRs, which respond to the neurotransmitter glutamate and therefore are of considerable interest as drug targets for the treatment of a range of diseases, including fragile X syndrome, autism, depression, anxiety, addiction and movement disorders. Structural studies to date have been restricted to the extracellular domain of mGlu₅, providing little understanding of the membrane-spanning signal transduction domain, and hindering drug discovery efforts.

Crystals of the mGlu5 transmembrane domain (StaR(569-836)-T4L) grown in lipidic cubic phase using 30nl LCP boli dispensed with a mosquito LCP. Image courtesy of Dr A.S. Doré, Heptares Therapeutics Ltd, Welwyn Garden City, UK.

In this scientific publication the scientists at Heptares describe the crystal structure of the transmembrane domain of mGlu₅ in complex with the negative allosteric modulator (NAM), mavoglurant. Heptares has used these new findings to identify several novel differentiated mGlu₅ NAM drug candidates with improved potency and pharmacokinetic properties compared to previous candidate molecules.

To help increase the accuracy, speed and throughput of crystallography screening, optimization and crystal production, TTP Labtech has engineered innovative automated liquid handling solutions, including the mosquito crystal and mosquito LCP, to significantly improve this process.

TTP Labtech’s mosquito LCP is used by most of the world class institutions and leading pharmaceutical and biotechnology companies for protein crystallization screening. It overcomes the common problems encountered with accurately dispensing the highly viscous LCP mixture used in membrane protein crystallization. It allows you to fully automate LCP set-ups accurately and repeatedly and the technology has played an important role in the determination of many protein structures, including some key GPCRs.

“As early adopters of the mosquito LCP, we have had a close collaborative relationship with Dr Doré’s team since 2010,” commented Joby Jenkins, global director of automation at TTP Labtech. “The huge success of Heptares in determining ground breaking GPCR structures has resulted in increased productivity and the need for additional mosquito LCP instruments. We are delighted that our liquid handlers have been, and will be, an integral part of their ongoing success.”