Summary information and primary citation
- PDB-id
-
5cbz;
DSSR-derived features in text and
JSON formats
- Class
- DNA binding protein-DNA
- Method
- X-ray (2.2 Å)
- Summary
- Ancmr DNA binding domain - (+)gre complex
- Reference
-
Hudson WH, Kossmann BR, de Vera IM, Chuo SW, Weikum ER,
Eick GN, Thornton JW, Ivanov IN, Kojetin DJ, Ortlund EA
(2016): "Distal
substitutions drive divergent DNA specificity among
paralogous transcription factors through subdivision of
conformational space."
Proc.Natl.Acad.Sci.USA, 113,
326-331. doi: 10.1073/pnas.1518960113.
- Abstract
- 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.
