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2014 ; 30
(12
): 521-8
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Engineering allostery
#MMPMID25306102
Raman S
; Taylor N
; Genuth N
; Fields S
; Church GM
Trends Genet
2014[Dec]; 30
(12
): 521-8
PMID25306102
show ga
Allosteric proteins have great potential in synthetic biology, but our limited
understanding of the molecular underpinnings of allostery has hindered the
development of designer molecules, including transcription factors with new
DNA-binding or ligand-binding specificities that respond appropriately to
inducers. Such allosteric proteins could function as novel switches in complex
circuits, metabolite sensors, or as orthogonal regulators for independent,
inducible control of multiple genes. Advances in DNA synthesis and
next-generation sequencing technologies have enabled the assessment of millions
of mutants in a single experiment, providing new opportunities to study
allostery. Using the classic LacI protein as an example, we describe a genetic
selection system using a bidirectional reporter to capture mutants in both
allosteric states, allowing the positions most crucial for allostery to be
identified. This approach is not limited to bacterial transcription factors, and
could reveal new mechanistic insights and facilitate engineering of other major
classes of allosteric proteins such as nuclear receptors, two-component systems,
G protein-coupled receptors, and protein kinases.
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