6DDR

Crystal Structure Analysis of the Epitope of an Anti-MICA Antibody

Summary for 6DDR

• Entry DOI: 10.2210/pdb6ddr/pdb
• Descriptor: Anti-MICA Fab fragment light chain clone 13A9, Anti-MICA Fab fragment heavy chain clone 13A9, MHC class I polypeptide-related sequence A, ... (7 entities in total)
• Functional Keywords: fab fragment-antigen complex, immunoglobulin domain, immune system
• Biological source: Mus musculus; More
• Total number of polymer chains: 3
• Total formula weight: 58476.07

Authors

Matsumoto, M.L. (deposition date: 2018-05-10, release date: 2018-10-24, Last modification date: 2024-11-06)

Primary citation

Lombana, T.N.,Matsumoto, M.L.,Berkley, A.M.,Toy, E.,Cook, R.,Gan, Y.,Du, C.,Schnier, P.,Sandoval, W.,Ye, Z.,Schartner, J.M.,Kim, J.,Spiess, C.
High-resolution glycosylation site-engineering method identifies MICA epitope critical for shedding inhibition activity of anti-MICA antibodies.
MAbs, 11:75-93, 2019

PubMed Abstract: As an immune evasion strategy, MICA and MICB, the major histocompatibility complex class I homologs, are proteolytically cleaved from the surface of cancer cells leading to impairment of CD8 + T cell- and natural killer cell-mediated immune responses. Antibodies that inhibit MICA/B shedding from tumors have therapeutic potential, but the optimal epitopes are unknown. Therefore, we developed a high-resolution, high-throughput glycosylation-engineered epitope mapping (GEM) method, which utilizes site-specific insertion of N-linked glycans onto the antigen surface to mask local regions. We apply GEM to the discovery of epitopes important for shedding inhibition of MICA/B and validate the epitopes at the residue level by alanine scanning and X-ray crystallography (Protein Data Bank accession numbers 6DDM (1D5 Fab-MICA*008), 6DDR (13A9 Fab-MICA*008), 6DDV (6E1 Fab-MICA*008). Furthermore, we show that potent inhibition of MICA shedding can be achieved by antibodies that bind GEM epitopes adjacent to previously reported cleavage sites, and that these anti-MICA/B antibodies can prevent tumor growth in vivo.

PubMed: 30307368
DOI: 10.1080/19420862.2018.1532767

Experimental method

X-RAY DIFFRACTION (1.9 Å)