PXD049976

PXD049976 is an original dataset announced via ProteomeXchange.

Title	Development and crystal structures of a more potent second-generation dual degrader of BCL-2 and BCL-xL
Description	Overexpression of BCL-xL and BCL-2 play key roles in tumorigenesis and cancer drug resistance. Advances in PROTAC technology facilitated recent development of the first BCL-xL/BCL-2 dual degrader, 753b, a VHL-based degrader with improved potency and reduced toxicity compared to previous small molecule inhibitors. Here, we determined crystal structures of VHL/753b/BCL-xL and VHL/753b/ BCL-2 ternary complexes. The two ternary complexes exhibit markedly different architectures that are accompanied by distinct networks of interactions at the VHL/PZ753b-linker/target interfaces. The importance of these interfacial contacts was validated via functional analysis and informed subsequent rational and structure-guided design focused on the 753b linker and BCL-2/BCL-xL warhead. This resulted in the design of a novel degrader, WH244, with enhanced potency to degrade BCL-xL/BCL-2 in cells. Using biophysical assays followed by in cell activities, we were able to explain the enhanced target degradation of BCL-2/BCL-xL in cells. Most PROTACs are empirically designed and lack structural studies, making it challenging to understand their modes of action and specificity. Our work presents a streamlined approach that combines rational design and structure-based insights backed with cell-based studies to develop effective PROTAC-based cancer therapeutics.
HostingRepository	PRIDE
AnnounceDate	2024-03-12
AnnouncementXML	Submission_2024-03-12_15:48:11.234.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Dongwen Lyu
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2024-02-20 14:35:18	ID requested
⏵ 1	2024-03-12 15:48:11	announced

Dataset with its publication pending

submitter keyword: PROTAC, crystal structure, ubiquitin, ternary complex, degrader, E3 ligase, BCL-xL/BCL-2

Dongwen Lyu
contact affiliation	UT Health San Antonio
contact email	lyud@uthscsa.edu
lab head
Dongwen Lyu
contact affiliation	UT Health San Antonio
contact email	lyud@uthscsa.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/2024/03/PXD049976

PRIDE project URI

• PRIDE
  1. PXD049976
     1. Label: PRIDE project
     2. Name: Development and crystal structures of a more potent second-generation dual degrader of BCL-2 and BCL-xL