Dissection of integrated readout reveals the structural thermodynamics of DNA selection by transcription factors.

Autor:	Vernon TN; Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA., Terrell JR; Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA., Albrecht AV; Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA., Germann MW; Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA; Department of Biology, Georgia State University, Atlanta, GA 30302, USA. Electronic address: mwg@gsu.edu., Wilson WD; Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA; Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, USA. Electronic address: wdw@gsu.edu., Poon GMK; Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA; Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, USA. Electronic address: gpoon@gsu.edu.
Jazyk:	angličtina
Zdroj:	Structure (London, England : 1993) [Structure] 2024 Jan 04; Vol. 32 (1), pp. 83-96.e4. Date of Electronic Publication: 2023 Dec 01.
DOI:	10.1016/j.str.2023.11.003
Abstrakt:	Nucleobases such as inosine have been extensively utilized to map direct contacts by proteins in the DNA groove. Their deployment as targeted probes of dynamics and hydration, which are dominant thermodynamic drivers of affinity and specificity, has been limited by a paucity of suitable experimental models. We report a joint crystallographic, thermodynamic, and computational study of the bidentate complex of the arginine side chain with a Watson-Crick guanine (Arg×GC), a highly specific configuration adopted by major transcription factors throughout the eukaryotic branches in the Tree of Life. Using the ETS-family factor PU.1 as a high-resolution structural framework, inosine substitution for guanine resulted in a sharp dissection of conformational dynamics and hydration and elucidated their role in the DNA specificity of PU.1. Our work suggests an under-exploited utility of modified nucleobases in untangling the structural thermodynamics of interactions, such as the Arg×GC motif, where direct and indirect readout are tightly integrated. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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