9ML8

Crystal structure of the SARS-CoV-2 RBD in complex with the rabbit M8b-B1 Fab

9ML8 の概要

• エントリーDOI: 10.2210/pdb9ml8/pdb
• 分子名称: Spike protein S1, M8b-B1 heavy chain, M8b-B1 light chain, ... (6 entities in total)
• 機能のキーワード: immune system, neutralizing antibody, viral protein-immune system complex, viral protein/immune system
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, 2019-nCoV, COVID-19 virus); 詳細
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 291684.89

構造登録者

Fan, C.,Bjorkman, P.J. (登録日: 2024-12-18, 公開日: 2025-06-04)

主引用文献

Fan, C.,Keeffe, J.R.,Malecek, K.E.,Cohen, A.A.,West Jr., A.P.,Baharani, V.A.,Rorick, A.V.,Gao, H.,Gnanapragasam, P.N.P.,Rho, S.,Alvarez, J.,Segovia, L.N.,Hatziioannou, T.,Bieniasz, P.D.,Bjorkman, P.J.
Cross-reactive sarbecovirus antibodies induced by mosaic RBD nanoparticles.
Proc.Natl.Acad.Sci.USA, 122:e2501637122-e2501637122, 2025

PubMed Abstract: Broad immune responses are needed to mitigate viral evolution and escape. To induce antibodies against conserved receptor-binding domain (RBD) regions of SARS-like betacoronavirus (sarbecovirus) spike proteins that recognize SARS-CoV-2 variants of concern and zoonotic sarbecoviruses, we developed mosaic-8b RBD nanoparticles presenting eight sarbecovirus RBDs arranged randomly on a 60-mer nanoparticle. Mosaic-8b immunizations protected animals from challenges from viruses whose RBDs were matched or mismatched to those on nanoparticles. Here, we describe neutralizing mAbs isolated from mosaic-8b-immunized rabbits, some on par with Pemgarda, the only currently FDA-approved therapeutic mAb. Deep mutational scanning, in vitro selection of spike resistance mutations, and single-particle cryo-electron microscopy structures of spike-antibody complexes demonstrated targeting of conserved RBD epitopes. Rabbit mAbs included critical D-gene segment RBD-recognizing features in common with human anti-RBD mAbs, despite rabbit genomes lacking an equivalent human D-gene segment, thus demonstrating that the immune systems of humans and other mammals can utilize different antibody gene segments to arrive at similar modes of antigen recognition. These results suggest that animal models can be used to elicit anti-RBD mAbs with similar properties to those raised in humans, which can then be humanized for therapeutic use, and that mosaic RBD nanoparticle immunization coupled with multiplexed screening represents an efficient way to generate and select broadly cross-reactive therapeutic pan-sarbecovirus and pan-SARS-CoV-2 variant mAbs.

PubMed: 40402246
DOI: 10.1073/pnas.2501637122

実験手法

X-RAY DIFFRACTION (2.4 Å)