PXD021132

PXD021132 is an original dataset announced via ProteomeXchange.

Title	Targeting of disease-linked mutations in PI3K gamma
Description	Using hydrogen deuterium exchange mass spectrometry (HDX-MS) and molecular dynamics we have identified mutation specific conformational changes, and provide a molecular framework for how they alter kinase activity.Many of the activating conformational changes mimicked previously described changes that occur upon membrane binding and allosteric inhibitor binding. We surveyed a diverse panel of PI3K inhibitors using HDX-MS and X-ray crystallography, and find that inhibitors that interact with the activation loop lead to allosteric conformational changes that partially mimic the R1021C mutation. Intriguingly, inhibitors that showed similar conformational changes to the activating mutant showed increased potency (~3 fold) for the mutant over wild type PI3K. Overall this work provides unique insight into the regulatory mechanisms that control PI3K kinase activity, and reveals a framework for the potential design of PI3K isoform and mutant selective inhibitors.
HostingRepository	PRIDE
AnnounceDate	2021-03-26
AnnouncementXML	Submission_2021-03-25_23:27:48.921.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	John Burke
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	impact HD

Revision	Datetime	Status	ChangeLog Entry
0	2020-08-26 02:21:38	ID requested
⏵ 1	2021-03-25 23:27:49	announced

Rathinaswamy MK, Gaieb Z, Fleming KD, Borsari C, Harris NJ, Moeller BE, Wymann MP, Amaro RE, Burke JE, disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors. Elife, 10():(2021) [pubmed]

submitter keyword: HDX-MS, PI3K gamma, PI3K, molecular dynamics, kinase assay, inhibitor

Dr. John E Burke
contact affiliation	University of Victoria
contact email	jeburke@uvic.ca
lab head
John Burke
contact affiliation	University of Victoria
contact email	jeburke@uvic.ca
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/2021/03/PXD021132

PRIDE project URI

• PRIDE
  1. PXD021132
     1. Label: PRIDE project
     2. Name: Targeting of disease-linked mutations in PI3K gamma