PXD036076 is an
original dataset announced via ProteomeXchange.
Dataset Summary
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 | 2024-10-22 |
AnnouncementXML | Submission_2024-10-22_05:40:07.649.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | SABAB HASAN KHAN |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | No PTMs are included in the dataset |
Instrument | Synapt MS |
Dataset History
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. |
Publication List
Dataset with its publication pending |
Keyword List
submitter keyword: LC-MSMS |
Contact List
C. Denise Okafor |
contact affiliation | Department of Biochemistry and Molecular Biology, Pennsylvania State University |
contact email | cdo5093@psu.edu |
lab head | |
SABAB HASAN KHAN |
contact affiliation | Pennsylvania State University |
contact email | shk5169@psu.edu |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD036076
- Label: PRIDE project
- Name: Ligand-induced shifts in conformational ensembles that predict transcriptional activation