8VR9

Structure of a synthetic antibody in complex with a class I MHC presenting a hapten-peptide conjugate

8VR9 の概要

• エントリーDOI: 10.2210/pdb8vr9/pdb
• EMDBエントリー: 43478
• 分子名称: HLA class I histocompatibility antigen, A alpha chain, Beta-2-microglobulin, GTPase KRas, N-terminally processed, ... (6 entities in total)
• 機能のキーワード: complex, synthetic antibody, mhc class i, covalently modified peptide, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 92845.17

構造登録者

Maso, L.,Bang, I.,Koide, S. (登録日: 2024-01-20, 公開日: 2024-09-04, 最終更新日: 2024-10-09)

主引用文献

Maso, L.,Rajak, E.,Bang, I.,Koide, A.,Hattori, T.,Neel, B.G.,Koide, S.
Molecular basis for antibody recognition of multiple drug-peptide/MHC complexes.
Proc.Natl.Acad.Sci.USA, 121:e2319029121-e2319029121, 2024

PubMed Abstract: The HapImmune platform exploits covalent inhibitors as haptens for creating major histocompatibility complex (MHC)-presented tumor-specific neoantigens by design, combining targeted therapies with immunotherapy for the treatment of drug-resistant cancers. A HapImmune antibody, R023, recognizes multiple sotorasib-conjugated KRAS(G12C) peptides presented by different human leukocyte antigens (HLAs). This high specificity to sotorasib, coupled with broad HLA-binding capability, enables such antibodies, when reformatted as T cell engagers, to potently and selectively kill sotorasib-resistant KRAS(G12C) cancer cells expressing different HLAs upon sotorasib treatment. The loosening of HLA restriction could increase the patient population that can benefit from this therapeutic approach. To understand the molecular basis for its unconventional binding capability, we used single-particle cryogenic electron microscopy to determine the structures of R023 bound to multiple sotorasib-peptide conjugates presented by different HLAs. R023 forms a pocket for sotorasib between the V and V domains, binds HLAs in an unconventional, angled way, with V making most contacts with them, and makes few contacts with the peptide moieties. This binding mode enables the antibody to accommodate different hapten-peptide conjugates and to adjust its conformation to different HLAs presenting hapten-peptides. Deep mutational scanning validated the structures and revealed distinct levels of mutation tolerance by sotorasib- and HLA-binding residues. Together, our structural information and sequence landscape analysis reveal key features for achieving MHC-restricted recognition of multiple hapten-peptide antigens, which will inform the development of next-generation therapeutic antibodies.

PubMed: 38781214
DOI: 10.1073/pnas.2319029121

実験手法

ELECTRON MICROSCOPY (3.06 Å)