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PDBsum entry 5cbx
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DNA binding protein/DNA
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PDB id
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5cbx
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References listed in PDB file
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Key reference
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Title
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Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space.
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Authors
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W.H.Hudson,
B.R.Kossmann,
I.M.De vera,
S.W.Chuo,
E.R.Weikum,
G.N.Eick,
J.W.Thornton,
I.N.Ivanov,
D.J.Kojetin,
E.A.Ortlund.
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Ref.
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Proc Natl Acad Sci U S A, 2016,
113,
326-331.
[DOI no: ]
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PubMed id
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Abstract
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Many genomes contain families of paralogs-proteins with divergent function that
evolved from a common ancestral gene after a duplication event. To understand
how paralogous transcription factors evolve divergent DNA specificities, we
examined how the glucocorticoid receptor and its paralogs evolved to bind
activating response elements [(+)GREs] and negative glucocorticoid response
elements (nGREs). We show that binding to nGREs is a property of the
glucocorticoid receptor (GR) DNA-binding domain (DBD) not shared by other
members of the steroid receptor family. Using phylogenetic, structural,
biochemical, and molecular dynamics techniques, we show that the ancestral DBD
from which GR and its paralogs evolved was capable of binding both nGRE and
(+)GRE sequences because of the ancestral DBD's ability to assume multiple
DNA-bound conformations. Subsequent amino acid substitutions in duplicated
daughter genes selectively restricted protein conformational space, causing this
dual DNA-binding specificity to be selectively enhanced in the GR lineage and
lost in all others. Key substitutions that determined the receptors' response
element-binding specificity were far from the proteins' DNA-binding interface
and interacted epistatically to change the DBD's function through DNA-induced
allosteric mechanisms. These amino acid substitutions subdivided both the
conformational and functional space of the ancestral DBD among the present-day
receptors, allowing a paralogous family of transcription factors to control
disparate transcriptional programs despite high sequence identity.
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