Heptares Therapeutics Limited

Antony Johannes Warne

Christopher Gordon Tate

Malcolm Peter Weir

Richard Henderson

Yoko Shibata

Francesca Magnani

Maria Josefa Serrano-Vega

Andrew Leslie

Byron Carpenter

Rony Nehmé

The invention relates to mutant G-protein coupled receptors with increased conformational stability, and methods of use thereof. In some aspects, polynucleotides encoding the mutant G-protein coupled receptors are provided. In some aspects, host cells comprising the polynucleotides are provided. In some aspects, the invention relates to crystallized forms of the mutant G-protein coupled receptors, and methods of preparing the same.

Mutant G-protein coupled receptors and methods for selecting them

The invention provides a mutant of a parent heterotrimeric G protein alpha (G&#x3b1;) subunit, which mutant (i) lacks at least one helix of the helical domain of the parent G&#x3b1; subunit; (ii) is capable of binding to a GPCR in the absence of a heterotrimeric G protein beta (G&#x3b2;) subunit and a heterotrimeric G protein gamma (G&#x3b3;) subunit; and (iii) has an amino acid sequence that contains one or more mutations compared to the amino acid sequence of the parent heterotrimeric G&#x3b1; subunit, which mutations are selected from a deletion, a substitution and an insertion.

G proteins

A method of producing a conformational specific binding partner of a GPCR, the method comprising: a) providing a mutant GPCR of a parent GPCR, wherein the mutant GPCR has increased stability in a particular conformation relative to the parent GPCR; b) providing a test compound; c) determining whether the test compound binds to the mutant GPCR when residing in a particular conformation; and d) isolating a test compound that binds to the mutant GPCR when residing in the particular formation. Methods of producing GPCRs with increased stability relative to a parent GPCR are also disclosed.

Methods for screening for binding partners of G-protein coupled receptors

The present invention relates in some aspects to mutant G protein coupled receptors (GPCRs) and methods for selecting those with increased stability. In certain aspects, the invention relates to the selection and preparation of mutant GPCRs which have increased stability under a particular condition compared to their respective parent proteins.

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Cambridge, United Kingdom

Antony Johannes Warne