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Innovative Technology Enables First Crystal Structure of mGlu5 Transmembrane Domain to be Determined

Published: Saturday, July 19, 2014
Last Updated: Saturday, July 19, 2014
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Several novel drug candidates have been identified to help treat specific neuropsychiatric disorders.

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 signalling 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.

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 users 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.

Jenkins continued, “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.”

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