Abstract
A major challenge in synthetic biology, particularly for mammalian systems, is the inclusion of adequate external control for the synthetic system activities. Control at the transcriptional level can be achieved by adaptation of bacterial repressor–operator systems (e.g., TetR), but altering the activity of a protein by controlling transcription is indirect and for longer half-life mRNAs, decreasing activity this way can be inconveniently slow. Where possible, direct modulation of protein activity by soluble ligands has many advantages, including rapid action. Decades of drug discovery and pharmacological research have uncovered detailed information on the interactions between large numbers of small molecules and their primary protein targets (as well as off-target secondary interactions), many of which have been well studied in mammals, including humans. In principle, this accumulated knowledge would be a powerful resource for synthetic biology. Here, we present SynPharm, a tool that draws together information from the pharmacological database GtoPdb and the structural database, PDB, to help synthetic biologists identify ligand-binding domains of natural proteins. Consequently, as sequence cassettes, these may be suitable for building into engineered proteins to confer small-molecule modulation on them. The tool has ancillary utilities which include assessing contact changes among different ligands in the same protein, predicting possible effects of genetic variants on binding residues, and insights into ligand cross-reactivity among species.
Highlights
Synthetic biology is a technology for engineering of new biological functions through the construction of novel genetic networks to realize novel metabolic, signaling, and developmental pathways.[1−5] Some synthetic biological systems use only natural proteins or achieve novel functions by combining proteins not normally found in the same cell or even the same species
Other systems involve the use of novel proteins, themselves typically including domains chosen from various natural proteins and coded into an engineered gene: an example is the SynNotch synthetic cell−cell signaling system.[6]
There is a clear need for synthetic biological devices to be subject to external controls, for example, to create adequate safeguards and to exert temporal and/or spatial control on a particular system
Summary
Synthetic biology is a technology for engineering of new biological functions through the construction of novel genetic networks to realize novel metabolic, signaling, and developmental pathways.[1−5] Some synthetic biological systems use only natural proteins (i.e., as represented by the Swiss-Prot canonical sequence for that species) or achieve novel functions by combining proteins not normally found in the same cell or even the same species. Other systems involve the use of novel proteins, themselves typically including domains chosen from various natural proteins and coded into an engineered gene: an example is the SynNotch synthetic cell−cell signaling system.[6] In many applications, there is a clear need for synthetic biological devices to be subject to external controls, for example, to create adequate safeguards and to exert temporal and/or spatial control on a particular system. This need is acute when the device is intended to be used in the general environment or in a medical implant. Control by rapidly diffusing small molecules would be useful and several novel controls of this type have been constructed, generally by a laborious process of selection from large libraries of protein variants.[11,12]
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