PXD034008

PXD034008 is an original dataset announced via ProteomeXchange.

Title	Structural mechanism of a drug-binding process involving a large conformational change of the protein target
Description	Structural biology studies indicate that proteins often undergo large conformational changes when binding small molecules, but atomic-level descriptions of binding events involving such changes have been elusive. A prominent example of binding accompanied by a large conformational change is the binding of Abl kinase to the cancer drug imatinib, a detailed understanding of which could potentially inform future drug-discovery efforts targeting kinases. Here, we report unguided molecular dynamics simulations of Abl-imatinib binding that start from an unbound state and ultimately reach a bound state that is highly consistent with known crystal structures of the Abl- imatinib complex. In the course of this process, we observed that imatinib first selectively engages Abl kinase in its autoinhibitory conformation. Consistent with inferences drawn from previous experimental studies, imatinib then induces a large conformational change of the protein, and this motion is captured in atomic detail by the simulations. Moreover, the simulations reveal a surprising local structural instability in the C-terminal lobe of Abl kinase during binding and, to a lesser degree, in the bound state. The unstable region, which is distal to the imatinib-binding site, includes a number of residues that, when mutated, confer resistance to imatinib therapy by an unknown mechanism. Using NMR, thermostability, and hydrogen-deuterium exchange (HDX) measurements, along with energetic estimates, we determined that these mutations likely destabilize the Abl kinase structure. These findings, along with the simulations, suggest that these mutations confer imatinib resistance by a previously undescribed mechanism in which they exacerbate structural instability in the C-terminal lobe to the degree that the imatinib-bound state is energetically unfavorable.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:44:36.192.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	2022-05-20 10:23:11	ID requested
1	2023-04-07 04:59:44	announced
⏵ 2	2023-11-14 08:44:39	announced	2023-11-14: Updated project metadata.

Ayaz P, Lyczek A, Paung Y, Mingione VR, Iacob RE, de Waal PW, Engen JR, Seeliger MA, Shan Y, Shaw DE, Structural mechanism of a drug-binding process involving a large conformational change of the protein target. Nat Commun, 14(1):1885(2023) [pubmed]

submitter keyword: HDX MS,Hydrogen exchange mass spectrometry, Molecular dynamics simulations

drug binding

Abl kinase

localized unfolding

imatinib resistance

John R. Engen
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/2023/04/PXD034008

PRIDE project URI

• PRIDE
  1. PXD034008
     1. Label: PRIDE project
     2. Name: Structural mechanism of a drug-binding process involving a large conformational change of the protein target