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Chiang, W.-H.

Publications and source records attributed to Chiang, W.-H..

2 recordsLinked to original sources
bioRxiv2022

Structural basis of transcriptional activation by the OmpR/PhoB-family response regulator PmrA

PmrA, an OmpR/PhoB-family response regulator, activates gene transcription responsible for polymyxin resistance in bacteria by recognizing promoters in which the canonical -35 element is replaced by the pmra-box, representing the PmrA recognition sequence. Here, we report a cryo-electron microscopy-derived structure of a bacterial PmrA-dependent transcription activation complex (TAC) containing a PmrA dimer, an RNA polymerase {sigma}70-holoenzyme (RNAPH), and the pbgP promoter DNA. Our structure reveals that the RNAPH mainly contacts the PmrA C-terminal DNA binding domain (DBD) via electrostatic interactions and reorients the DBD three base pairs upstream of the pmra-box, resulting in a dynamic TAC conformation. In vivo assays show that substitution of PmrA DNA-recognition residues eliminated its transcriptional activity, but variants with altered RNAPH-interacting residues exhibited elevated transcriptional activity. Our study indicates that both PmrA recognition-induced DNA distortion and PmrA promoter escape play important roles in its transcriptional activation.

biophysics↗
bioRxiv2019

Drug Recommendation toward Safe Polypharmacy

Adverse drug reactions (ADRs) induced from high-order drug-drug interactions (DDIs) due to polypharmacy - simultaneous use of multiple drugs - represent a significant public health problem. Unfortunately, computational effects to facilitate future polypharmacy, particularly to assist safe multidrug prescription, are still in their infancy. We formally formulate the to-avoid and safe drug recommendation problems when multiple drugs have been taken simultaneously. We develop a joint model with a recommendation component and an ADR label prediction component to recommend for a prescription a set of to-avoid/safe drugs that will induce/will not induce ADRs if taken together with the prescription. We also develop real drug-drug interaction datasets and corresponding evaluation protocols.

bioinformatics↗