8QXC

Crystal structure of antibody Fab MIL-3 with PenG-Lys

Summary for 8QXC

• Entry DOI: 10.2210/pdb8qxc/pdb
• Descriptor: Heavy chain of FAB MIL-3, Light chain of FAB MIL-3, (2R,4S)-2-[(1R)-2-[[(5S)-5-acetamido-6-oxidanyl-6-oxidanylidene-hexyl]amino]-2-oxidanylidene-1-(2-phenylethanoylamino)ethyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid, ... (4 entities in total)
• Functional Keywords: fab, penicillin, peng, immune system
• Biological source: Mus musculus; More
• Total number of polymer chains: 6
• Total formula weight: 164160.94

Authors

Moynie, L.,Naismith, J.H. (deposition date: 2023-10-24, release date: 2024-07-31, Last modification date: 2024-11-13)

Primary citation

Deimel, L.P.,Moynie, L.,Sun, G.,Lewis, V.,Turner, A.,Buchanan, C.J.,Burnap, S.A.,Kutuzov, M.,Kobras, C.M.,Demyaneko, Y.,Mohammed, S.,Stracy, M.,Struwe, W.B.,Baldwin, A.J.,Naismith, J.,Davis, B.G.,Sattentau, Q.J.
Covalent penicillin-protein conjugates elicit anti-drug antibodies that are clonally and functionally restricted.
Nat Commun, 15:6851-6851, 2024

PubMed Abstract: Many archetypal and emerging classes of small-molecule therapeutics form covalent 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 probe the B and T cell determinants of drug-specific IgG responses to such conjugates in mice. Deep B cell 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.

PubMed: 39127707
DOI: 10.1038/s41467-024-51138-7

Experimental method

X-RAY DIFFRACTION (2.3 Å)