Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Molecular basis for antibody recognition of multiple drug-peptide/MHC complexes.
Journal, issue, pages	Proc Natl Acad Sci U S A, Vol. 121, Issue 22, Page e2319029121, Year 2024
Publish date	May 28, 2024
Authors	Lorenzo Maso / Epsa Rajak / Injin Bang / Akiko Koide / Takamitsu Hattori / Benjamin G Neel / Shohei Koide /
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 ...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.
External links	Proc Natl Acad Sci U S A / PubMed:38781214 / PubMed Central
Methods	EM (single particle)
Resolution	3.06 - 3.25 Å
Structure data	43478 8vr9 EMDB-43478, PDB-8vr9: Structure of a synthetic antibody in complex with a class I MHC presenting a hapten-peptide conjugate Method: EM (single particle) / Resolution: 3.06 Å 43479 8vra EMDB-43479, PDB-8vra: Structure of a synthetic antibody in complex with a class I MHC presenting a hapten-peptide conjugate Method: EM (single particle) / Resolution: 3.12 Å 43480 8vrb EMDB-43480, PDB-8vrb: Structure of a synthetic antibody in complex with a class I MHC presenting a hapten-peptide conjugate Method: EM (single particle) / Resolution: 3.25 Å
Chemicals	ChemComp-MOV: AMG 510 (bound form)
Source	homo sapiens (human)
Keywords	IMMUNE SYSTEM / Complex / Synthetic antibody / MHC class I / covalently modified peptide