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primary topic: Molecular mechanisms underlying allosteric behavior of Escherichia coli DgoR, a GntR/FadR family transcriptional regulator

Molecular mechanisms underlying allosteric behavior of Escherichia coli DgoR, a GntR/FadR family transcriptional regulator
type: AcademicArticle
type: Article
abstract: GntR/FadR family featuring an N-terminal winged helix-turn-helix DNA-binding domain and a C-terminal α-helical effector-binding and oligomerization domain constitutes one of the largest families of transcriptional regulators. Several GntR/FadR regulators govern the metabolism of sugar acids, carbon sources implicated in bacterial-host interactions. Although effectors are known for a few sugar acid regulators, the unavailability of relevant structures has left their allosteric mechanism unexplored. Here, using DgoR, a transcriptional repressor of d-galactonate metabolism in Escherichia coli, as a model, and its superrepressor alleles, we probed allostery in a GntR/FadR family sugar acid regulator. Genetic and biochemical studies established compromised response to d-galactonate as the reason for the superrepressor behavior of the mutants: T180I does not bind d-galactonate, and while A97V, S171L and M188I bind d-galactonate, effector binding does not induce a conformational change required for derepression, suggesting altered allostery. For mechanistic insights into allosteric communication, we performed simulations of the modeled DgoR structure in different allosteric states for both the wild-type and mutant proteins. We found that each mutant exhibits unique dynamics disrupting the intrinsic allosteric communication pathways, thereby impacting DgoR function. We finally validated the allosteric communication model by testing in silico predictions with experimental data.
date: 2025-01
volume: 53
issue: 1
author list: authors
type: EPrint
type: ArticleEPrint
is part of: repository

Oxford University Press (OUP)
type: Organization

Nucleic Acids Res.
type: Collection

Rachna Chaba
type: Person
given name: Rachna
family name: Chaba

Krishna Upadhayay
type: Person
given name: Krishna
family name: Upadhayay

Monika Sharma
type: Person
given name: Monika
family name: Sharma

Shivam Singla
type: Person
given name: Shivam
family name: Singla

Rajesh Mishra
type: Person
given name: Rajesh
family name: Mishra

Garima Arya
type: Person
given name: Garima
family name: Arya

Akhil Pratap
type: Person
given name: Akhil
family name: Pratap

Swati Singh
type: Person
given name: Swati
family name: Singh

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primary topic: Molecular mechanisms underlying allosteric behavior of Escherichia coli DgoR, a GntR/FadR family transcriptional regulator