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Abstract We describe the concept and roadmap of an engineered electronic nose with specificity towards analytes that differ by as little as one carbon atom, and sensitivity of being able to electrically register a single molecule of analyte. The analyte could be anything that natural noses can detect, e.g. trinitrotoluene (TNT), cocaine, aromatics, volatile organic compounds etc. The strategy envisioned is to genetically engineer a fused olfactory odorant receptor (odorant receptor (OR), a membrane-bound G-protein coupled receptor (GPCR) with high selectivity) to an ion channel protein, which opens in response to binding of the ligand to the OR. The lipid bilayer supporting the fused sensing protein would be intimately attached to a nanowire or nanotube network (either via a covalent tether or a non-covalent physisorption process), which would electrically detect the opening of the ion channel, and hence the binding of a single ligand to a single OR protein domain. Three man-made technological advances: (1) fused GPCR to ion channel protein, (2) nanowire sensing of single ion channel activity, and (3) lipid bilayer to nanotube/nanowire tethering chemistry and on natural technology (sensitivity and selectivity of OR domains to specific analytes) each have been demonstrated and/or studied independently. The combination of these three technological advances and the result of millions of years of evolution of OR proteins would enable the goal of single molecule sensing with specificity towards analytes that differ by as little as one carbon atom. This is both a review of the past and a vision of the future.
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Structure and dynamics determine G protein coupling specificity at a class A GPCR
G protein coupled receptors (GPCRs) exhibit varying degrees of selectivity for different G protein isoforms. Despite the abundant structures of GPCR-G protein complexes, little is known about the mechanism of G protein coupling specificity. The β2-adrenergic receptor is an example of GPCR with high selectivity for Gαs, the stimulatory G protein for adenylyl cyclase, and much weaker for the Gαi family of G proteins inhibiting adenylyl cyclase. By developing a new Gαi-biased agonist (LM189), we provide structural and biophysical evidence supporting that distinct conformations at ICL2 and TM6 are required for coupling of the different G protein subtypes Gαs and Gαi. These results deepen our understanding of G protein specificity and bias and can accelerate the design of ligands that select for preferred signaling pathways.
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- Award ID(s):
- 1942957
- PAR ID:
- 10569294
- Publisher / Repository:
- bioRxiv
- Date Published:
- Format(s):
- Medium: X
- Institution:
- bioRxiv
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Posted Content:
- https://doi.org/10.1101/2024.03.28.587240
