PXD052026 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Covalent penicillin-protein conjugates elicit anti-drug antibodies that are clonally and functionally restricted |
Description | Many archetypal and emerging classes of small-molecule therapeutics form covalent 38 protein adducts. In vivo, both the resulting conjugates and their off-target side conjugates have the potential to elicit antibodies, with implications for allergy and drug sequestration. Although β-lactam antibiotics are a drug class long associated with these immunological phenomena, the molecular underpinnings of off-target drug protein conjugation and consequent drug-specific immune responses remain incomplete. Here, using the classical β-lactam penicillin G (PenG) we have now probed the B and T cell determinants of drug-specific IgG responses to such conjugates in mice. Deep clonotyping reveals a dominant murine clonal antibody class encompassing phylogenetically-related IGHV1, IGHV5 and IGHV10 subgroup gene segments. Protein NMR and x-ray structural analyses reveal that these drive structurally convergent binding modes in adduct-specific antibody clones. Their common primary recognition mechanisms of the penicillin side-chain moiety (phenylacetamide in PenG)—regardless of CDRH3 length—limits cross-reactivity against other β-lactam antibiotics. This immunogenetics-guided discovery of the limited binding solutions available to antibodies against side products of an archetypal covalent inhibitor now suggests future potential strategies for the ‘germline-guided reverse engineering’ of such drugs away from unwanted immune responses. |
HostingRepository | PRIDE |
AnnounceDate | 2024-10-22 |
AnnouncementXML | Submission_2024-10-22_06:53:22.341.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Sean Burnap |
SpeciesList | scientific name: Gallus gallus (Chicken); NCBI TaxID: 9031; scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | carbamoylated residue; acetylated residue; monohydroxylated residue |
Instrument | Q Exactive HF |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2024-05-06 10:49:55 | ID requested | |
1 | 2024-08-08 10:10:44 | announced | |
⏵ 2 | 2024-10-22 06:53:22 | announced | 2024-10-22: Updated project metadata. |
Publication List
Keyword List
submitter keyword: B-Lactam,Proteomics |
Contact List
Weston Struwe |
contact affiliation | Univeristy of Oxford |
contact email | weston.struwe@bioch.ox.ac.uk |
lab head | |
Sean Burnap |
contact affiliation | University of Oxford |
contact email | sean.burnap@bioch.ox.ac.uk |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD052026
- Label: PRIDE project
- Name: Covalent penicillin-protein conjugates elicit anti-drug antibodies that are clonally and functionally restricted