PXD036076-1

PXD036076 is an original dataset announced via ProteomeXchange.

Title	Ligand-induced shifts in conformational ensembles that predict transcriptional activation
Description	Nuclear receptors function as ligand-regulated transcription factors whose ability to regulate diverse physiological processes is closely linked with conformational changes induced upon ligand binding. Understanding how conformational populations of nuclear receptors are shifted by various ligands could illuminate strategies for the design of synthetic modulators to regulate specific transcriptional programs. Here, we investigate ligand-induced conformational changes using a reconstructed, ancestral nuclear receptor. By making substitutions at a key position, we engineer receptor variants with altered ligand specificities. We use atomistic molecular dynamics (MD) simulations with enhanced sampling to generate ensembles of wildtype and engineered receptors in combination with multiple ligands, followed by conformational analysis and prediction of ligand activity. We combine cellular and biophysical experiments to allow correlation of MD-based predictions with functional ligand profiles, as well as elucidation of mechanisms underlying altered transcription in receptor variants. We determine that conformational ensembles accurately predict ligand responses based on observed population shifts, even within engineered receptors that were constitutively active or transcriptionally unresponsive in experiments. These studies provide a platform which will allow structural characterization of physiologically-relevant conformational ensembles, as well as provide the ability to design and predict transcriptional responses in novel ligands.
HostingRepository	PRIDE
AnnounceDate	2022-10-12
AnnouncementXML	Submission_2022-10-12_09:26:38.104.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	SABAB HASANKHAN
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Synapt MS

Revision	Datetime	Status	ChangeLog Entry
0	2022-08-16 05:51:10	ID requested
⏵ 1	2022-10-12 09:26:38	announced
2	2024-10-22 05:40:08	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: LC-MSMS

C. DeniseOkafor
contact affiliation	Department of Biochemistry and Molecular Biology, Pennsylvania State University
contact email	cdo5093@psu.edu
lab head
SABAB HASANKHAN
contact affiliation	Pennsylvania State University
contact email	shk5169@psu.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/10/PXD036076

PRIDE project URI

• PRIDE
  1. PXD036076
     1. Label: PRIDE project
     2. Name: Ligand-induced shifts in conformational ensembles that predict transcriptional activation