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Molecular basis for coordinating secondary metabolite production by bacterial and plant signaling molecules

ABSTRACT: The production of secondary metabolites is one of the major mechanisms for beneficial rhizobacteria to antagonize plant pathogens. However, simultaneously producing large quantities of different secondary metabolites can pose great metabolic burdens and exerts a significant fitness cost on the producers. Here, we showed that PhlH from the rhizobacterium Pseudomonas fluorescens is a TetR-family regulator that plays a central role in coordinating biosynthesis of several secondary metabolites including 2,4-diacetylphloroglucinol (2,4-DAPG), mupirocin, and pyoverdine. Structures of PhlH in both its apo-form and 2,4-DAPG-bound were also presented, elucidating its ligand-recognizing and allosteric switching mechanisms. The ligand 2,4-DAPG was fully buried in a long hydrophobic interior tunnel and subsequent docking and mutagenesis analysis confirmed that this tunnel could also be occupied by the plant flavonoid phloretin, providing a structural basis for the ligand-binding promiscuity in PhlH. Moreover, dissociation of 2,4-DAPG from the ligand-binding domain (LBD) alone was sufficient to allosterically trigger a pendulum-like movement of the DNA-binding domains (DBD) within the PhlH dimer, leading to a closed to open conformational transition. Molecular dynamics simulation further confirmed that these two distinct conformational states were stabilized by specific hydrogen bonding interactions and disruption of these hydrogen bonds had profound effects on signal transmission from LBD to DBD. These findings revealed a potential route of allosteric signal transduction, which is well-conserved in numerous PhlH-like regulators and provides novel insights into ligand-triggered conformational switching of TetR-family regulators.

ORGANISM(S): Pseudomonas Fluorescens F113

SUBMITTER: Yongxing He

PROVIDER: PXD025403 | iProX | Thu Apr 15 00:00:00 BST 2021

REPOSITORIES: iProX

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Molecular basis for coordinating secondary metabolite production by bacterial and plant signaling molecules.

Zhang Nannan N Wu Jin J Zhang Siping S Yuan Maoran M Xu Hang H Li Jie J Zhang Pingping P Wang Mingzhu M Kempher Megan L ML Tao Xuanyu X Zhang Li-Qun LQ Ge Honghua H He Yong-Xing YX

The Journal of biological chemistry 20220511 6

The production of secondary metabolites is a major mechanism used by beneficial rhizobacteria to antagonize plant pathogens. These bacteria have evolved to coordinate the production of different secondary metabolites due to the heavy metabolic burden imposed by secondary metabolism. However, for most secondary metabolites produced by bacteria, it is not known how their biosynthesis is coordinated. Here, we showed that PhlH from the rhizobacterium Pseudomonas fluorescens is a TetR-family regulato ...[more]

PMID: 35568198

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Project description:Haffez2017 - RAR interaction with synthetic analogues This model is described in the article: The molecular basis of the interactions between synthetic retinoic acid analogues and the retinoic acid receptors Hesham Haffez, David R. Chisholm, Roy Valentine, Ehmke Pohl, Christopher Redfern and Andrew Whiting MedChemComm Abstract: All-trans-retinoic acid (ATRA) and its synthetic analogues EC23 and EC19 direct cellular differentiation by interacting as ligands for the retinoic acid receptor (RARÎ±, Î² and Î³) family of nuclear receptor proteins. To date, a number of crystal structures of natural and synthetic ligands complexed to their target proteins have been solved, providing molecular level snap-shots of ligand binding. However, a deeper understanding of receptor and ligand flexibility and conformational freedom is required to develop stable and effective ATRA analogues for clinical use. Therefore, we have used molecular modelling techniques to define RAR interactions with ATRA and two synthetic analogues, EC19 and EC23, and compared their predicted biochemical activities to experimental measurements of relative ligand affinity and recruitment of coactivator proteins. A comprehensive molecular docking approach that explored the conformational space of the ligands indicated that ATRA is able to bind the three RAR proteins in a number of conformations with one extended structure being favoured. In contrast the biologically-distinct isomer, 9-cis-retinoic acid (9CRA), showed significantly less conformational flexibility in the RAR binding pockets. These findings were used to inform docking studies of the synthetic retinoids EC23 and EC19, and their respective methyl esters. EC23 was found to be an excellent mimic for ATRA, and occupied similar binding modes to ATRA in all three target RAR proteins. In comparison, EC19 exhibited an alternative binding mode which reduces the strength of key polar interactions in RARÎ±/Î³ but is well-suited to the larger RARÎ² binding pocket. In contrast, docking of the corresponding esters revealed the loss of key polar interactions which may explain the much reduced biological activity. Our computational results were complemented using an in vitro binding assay based on FRET measurements, which showed that EC23 was a strongly binding, pan-agonist of the RARs, while EC19 exhibited specificity for RARÎ², as predicted by the docking studies. These findings can account for the distinct behaviour of EC23 and EC19 in cellular differentiation assays, and additionally, the methods described herein can be further applied to the understanding of the molecular basis for the selectivity of different retinoids to RARÎ±, Î² and Î³. This model is hosted on BioModels Database and identified by: BIOMD0000000629. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

Molecular basis for coordinating secondary metabolite production by bacterial and plant signaling molecules

Publications

Molecular basis for coordinating secondary metabolite production by bacterial and plant signaling molecules.

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