PXD031099

PXD031099 is an original dataset announced via ProteomeXchange.

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

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.

Dataset with its publication pending

submitter keyword: LRH-1, HDX-MS

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

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/2022/05/PXD031099

PRIDE project URI

• PRIDE
  1. PXD031099
     1. Label: PRIDE project
     2. Name: Selective modulation of nuclear receptor LRH-1 through target-ing buried and surface regions of the binding pocket