5CC1

S425G Glucocorticoid receptor DNA binding domain - (+)GRE complex

Summary for 5CC1

• Entry DOI: 10.2210/pdb5cc1/pdb
• Descriptor: Glucocorticoid receptor, DNA (5'-D(*CP*CP*AP*GP*AP*AP*CP*AP*GP*AP*GP*TP*GP*TP*TP*CP*TP*G)-3'), DNA (5'-D(*TP*CP*AP*GP*AP*AP*CP*AP*CP*TP*CP*TP*GP*TP*TP*CP*TP*G)-3'), ... (5 entities in total)
• Functional Keywords: dna binding protein, dna binding protein-dna complex, dna binding protein/dna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 73456.70

Authors

Hudson, W.H.,Weikum, E.A.,Ortlund, E.A. (deposition date: 2015-07-01, release date: 2015-12-23, Last modification date: 2024-03-06)

Primary citation

Hudson, W.H.,Kossmann, B.R.,de Vera, I.M.,Chuo, S.W.,Weikum, E.R.,Eick, G.N.,Thornton, J.W.,Ivanov, I.N.,Kojetin, D.J.,Ortlund, E.A.
Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space.
Proc.Natl.Acad.Sci.USA, 113:326-331, 2016

PubMed 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.

PubMed: 26715749
DOI: 10.1073/pnas.1518960113

Experimental method

X-RAY DIFFRACTION (2.302 Å)