PXD056009-1

PXD056009 is an original dataset announced via ProteomeXchange.

Title	Development of mirror-image monobodies targeting the oncogenic BCR::ABL1 kinase
Description	Mirror-image proteins, composed of D-amino acids, are an attractive therapeutic modality, as they exhibit high metabolic stability and lack immunogenicity. Development of mirror-image binding proteins is achieved through chemical synthesis of D-target proteins, phage display library selection of L-binders and chemical synthesis of (mirror-image) D binders that consequently bind the physiological L-targets. Monobodies are well-established synthetic (L )binding proteins and their small size (~90 residues) and lack of endogenous cysteine residues make them particularly accessible to chemical synthesis. Here, we developed monobodies with nanomolar binding affinities against the D-SH2 domain of the leukemic tyrosine kinase BCR::ABL1. Two crystal structures of heterochiral monobody-SH2 complexes revealed targeting of the pY binding pocket by an unconventional binding mode. We then prepared potent D-monobodies by either ligating two chemically synthesized D-peptides or by self-assembly without ligation. Their proper folding and stability were determined and high affinity binding to the L-target was shown. D-monobodies were protease-resistant, showed long-term plasma stability, inhibited BCR::ABL1 kinase activity and bound BCR::ABL1 in cells and (to some extent in) cell lysates with high selectivity. Hence, we demonstrate that functional D monobodies can be developed readily. Our work represents an important step towards the possible future therapeutic use of D-monobodies when combined with emerging methods to enable cytoplasmic delivery of monobodies.
HostingRepository	PRIDE
AnnounceDate	2024-10-28
AnnouncementXML	Submission_2024-10-28_07:54:30.009.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Uwe Linne
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2024-09-19 03:38:25	ID requested
⏵ 1	2024-10-28 07:54:30	announced

Dataset with its publication pending

submitter keyword: monobodies, oncogenic BCR::ABL1 kinase,Mirror-image-monobodies

Dr. Uwe Linne
contact affiliation	Philipps-University Marburg Faculty of Chemistry Core Facility for Mass Spectrometry Hans-Meerwein-Str. 4 35032 Marburg
contact email	linneu@staff.uni-marburg.de
lab head
Uwe Linne
contact affiliation	Head of Core Facility Mass Spectrometry, Faculty of Chemistry, Philipps-University Marburg
contact email	linneu@staff.uni-marburg.de
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/2024/10/PXD056009

PRIDE project URI

• PRIDE
  1. PXD056009
     1. Label: PRIDE project
     2. Name: Development of mirror-image monobodies targeting the oncogenic BCR::ABL1 kinase