PXD025209-1

PXD025209 is an original dataset announced via ProteomeXchange.

Title	Structure of the phosphoinositide 3-kinase p110-p101 complex reveals molecular mechanism of GPCR activation
Description	The class IB phosphoinositide 3-kinase (PI3K), PI3K, is a master regulator of immune cell function, and is a promising drug target for both inflammatory diseases and cancer. Critical to PI3K function is the association of the p110 catalytic subunit to either a p101 or p84 regulatory subunit, which mediates regulation by G-protein coupled receptors (GPCRs). Here, we report the first structure of a heterodimeric PI3K complex, p110-p101. This structure revealed a unique mode of assembly of catalytic and regulatory subunits distinct from that of other class I PI3K complexes. Multiple oncogenic mutations mapped to these novel interfaces led to increased activation by G. p101 mediates activation through its G binding domain, recruiting the complex to the membrane and allowing for engagement of a secondary site in p110. A nanobody that specifically binds to this p101-G interface blocks activation providing a novel tool to study p101-specific signaling events in vivo.
HostingRepository	PRIDE
AnnounceDate	2021-09-22
AnnouncementXML	Submission_2021-09-22_10:21:33.524.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	2021-04-06 06:14:53	ID requested
⏵ 1	2021-09-22 10:21:34	announced
2	2024-10-22 05:29:32	announced	2024-10-22: Updated project metadata.

Rathinaswamy MK, Dalwadi U, Fleming KD, Adams C, Stariha JTB, Pardon E, Baek M, Vadas O, DiMaio F, Steyaert J, Hansen SD, Yip CK, Burke JE, -p101 complex reveals molecular mechanism of GPCR activation. Sci Adv, 7(35):(2021) [pubmed]

submitter keyword: PIK3g, HDX, cryo-EM, GPCR

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/2021/09/PXD025209

PRIDE project URI

• PRIDE
  1. PXD025209
     1. Label: PRIDE project
     2. Name: Structure of the phosphoinositide 3-kinase p110-p101 complex reveals molecular mechanism of GPCR activation