PXD031099 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Selective modulation of nuclear receptor LRH-1 through target-ing buried and surface regions of the binding pocket |
Description | Liver receptor homolog-1 (LRH-1) is a phospholipid-sensing nuclear receptor that has shown promise as a target for alleviat-ing intestinal inflammation and disease states characterized by metabolic dysregulation in the liver. LRH-1 contains an unu-sually large ligand binding pocket, and generating synthetic modulators has been challenging. Leveraging a hexahydropen-talene (6HP) core, we have had recent success in generating potent and efficacious agonists through two distinct strategies. We targeted residues deep within the pocket to enhance compound binding, while residues at the mouth of the pocket were targeted to mimic interactions made by endogenous phospholipids. Here, we unite these two designs into one hybrid mole-cule that is the most potent LRH-1 agonist to date. Through a combination of global transcriptomic, biochemical, and struc-tural studies, we show that selective modulation can be driven through contacting deep vs. surface polar regions in the pock-et. While deep pocket contacts convey high-affinity, contacts with the pocket mouth dominate allostery and provide a phos-pholipid-like transcriptional response in cultured cells. |
HostingRepository | PRIDE |
AnnounceDate | 2023-11-14 |
AnnouncementXML | Submission_2023-11-14_08:54:34.846.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Valentine Courouble |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | No PTMs are included in the dataset |
Instrument | Q Exactive HF; Q Exactive |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2022-01-19 09:39:23 | ID requested | |
1 | 2022-05-04 05:45:09 | announced | |
⏵ 2 | 2023-11-14 08:54:35 | announced | 2023-11-14: Updated project metadata. |
Publication List
Dataset with its publication pending |
Keyword List
submitter keyword: LRH-1, HDX-MS |
Contact List
Patrick Griffin |
contact affiliation | Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, USA. |
contact email | pgriffin@scripps.edu |
lab head | |
Valentine Courouble |
contact affiliation | Scripps Research |
contact email | vcouroub@scripps.edu |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD031099
- Label: PRIDE project
- Name: Selective modulation of nuclear receptor LRH-1 through target-ing buried and surface regions of the binding pocket