PXD020029-1

PXD020029 is an original dataset announced via ProteomeXchange.

Title	Differential impact of BTK active site inhibitors on the conformational state of full-length BTK
Description	Bruton’s tyrosine kinase (BTK) is targeted in the treatment of B-cell disorders including leukemias and lymphomas. Currently approved BTK inhibitors, including Ibrutinib, a first-in-class covalent inhibitor of BTK, bind directly to the kinase active site. While effective at blocking the catalytic activity of BTK, consequences of drug binding on the global conformation of full-length BTK are unknown. Here we uncover a range of conformational effects in full-length BTK induced by a panel of active site inhibitors, including unexpected shifts in the conformational equilibria of the regulatory domains. Additionally, we find that a remote Ibrutinib resistance mutation, T316A in the BTK SH2 domain, drives spurious BTK activity by destabilizing the compact autoinhibitory conformation of full-length BTK, shifting the conformational ensemble away from the autoinhibited form. Future development of BTK inhibitors will need to consider long-range allosteric consequences of inhibitor binding, including the emerging application of these BTK inhibitors in treating COVID-19.
HostingRepository	PRIDE
AnnounceDate	2020-11-25
AnnouncementXML	Submission_2020-11-24_23:35:06.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	John R. Engen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Synapt MS

Revision	Datetime	Status	ChangeLog Entry
0	2020-06-26 03:15:20	ID requested
⏵ 1	2020-11-24 23:35:07	announced

Joseph RE, Amatya N, Fulton DB, Engen JR, Wales TE, Andreotti A, Differential impact of BTK active site inhibitors on the conformational state of full-length BTK. Elife, 9():(2020) [pubmed]

submitter keyword: Bruton’s Tyrosine Kinase

Ibrutinib

Dasatinib

GDC-0853

CC-292

CGI1746

drug resistance

SH2 domain

conformational selection

allostery

HDX-MS

hydrogen deuterium exchange mass spectrometry

John R. Enegn
contact affiliation	Department of Chemistry & Chemical Biology, Northeastern University
contact email	j.engen@northeastern.edu
lab head
John R. Engen
contact affiliation	Northeastern University
contact email	j.engen@northeastern.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/2020/11/PXD020029

PRIDE project URI

• PRIDE
  1. PXD020029
     1. Label: PRIDE project
     2. Name: Differential impact of BTK active site inhibitors on the conformational state of full-length BTK