PXD050013-1
PXD050013 is an original dataset announced via ProteomeXchange.
Dataset Summary
| 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 | MassIVE |
| AnnounceDate | 2024-03-12 |
| AnnouncementXML | Submission_2024-03-12_11:27:42.732.xml |
| DigitalObjectIdentifier | |
| ReviewLevel | Non peer-reviewed dataset |
| DatasetOrigin | Original dataset |
| RepositorySupport | Unsupported dataset by repository |
| PrimarySubmitter | Susan T. Weintraub |
| SpeciesList | scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606; |
| ModificationList | Carbamidomethyl |
| Instrument | Orbitrap Exploris 480 |
Dataset History
| Revision | Datetime | Status | ChangeLog Entry |
|---|---|---|---|
| 0 | 2024-02-21 11:52:56 | ID requested | |
| ⏵ 1 | 2024-03-12 11:27:43 | announced |
Publication List
| no publication |
Keyword List
| submitter keyword: PROTAC, ubiquitin, E3 ligase, ternary complex, BCL-xL/BCL-2, crystal structure, degrader |
Contact List
| Daohong Zhou, M.D. | |
|---|---|
| contact affiliation | The University of Texas Health Science Center at San Antonio |
| contact email | zhoud@uthscsa.edu |
| lab head | |
| Susan T. Weintraub | |
| contact affiliation | UT Health Science Center San Antonio |
| contact email | weintraub@uthscsa.edu |
| dataset submitter | |
Full Dataset Link List
| MassIVE dataset URI |
| 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://massive.ucsd.edu/v07/MSV000094144/ |
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