7KHF

CryoEM structure of LILRB1 D3D4 domain-inserted antibody MDB1 Fab in complex with Plasmodium RIFIN (PF3D7_1373400) V2 domain

Summary for 7KHF

• Entry DOI: 10.2210/pdb7khf/pdb
• Related: 7KFK
• EMDB information: 22879
• Descriptor: MDB1 Fab heavy chain, MDB1 Fab light chain, Rifin, ... (5 entities in total)
• Functional Keywords: lilrb1, rifin, malaria, receptor-inserted antibody, mdb1, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 6
• Total formula weight: 171491.72

Authors

Xu, K.,Kwong, P.D. (deposition date: 2020-10-21, release date: 2021-03-31, Last modification date: 2024-10-16)

Primary citation

Chen, Y.,Xu, K.,Piccoli, L.,Foglierini, M.,Tan, J.,Jin, W.,Gorman, J.,Tsybovsky, Y.,Zhang, B.,Traore, B.,Silacci-Fregni, C.,Daubenberger, C.,Crompton, P.D.,Geiger, R.,Sallusto, F.,Kwong, P.D.,Lanzavecchia, A.
Structural basis of malaria RIFIN binding by LILRB1-containing antibodies.
Nature, 592:639-643, 2021

PubMed Abstract: Some Plasmodium falciparum repetitive interspersed families of polypeptides (RIFINs)-variant surface antigens that are expressed on infected erythrocytes-bind to the inhibitory receptor LAIR1, and insertion of DNA that encodes LAIR1 into immunoglobulin genes generates RIFIN-specific antibodies. Here we address the general relevance of this finding by searching for antibodies that incorporate LILRB1, another inhibitory receptor that binds to β2 microglobulin and RIFINs through their apical domains. By screening plasma from a cohort of donors from Mali, we identified individuals with LILRB1-containing antibodies. B cell clones isolated from three donors showed large DNA insertions in the switch region that encodes non-apical LILRB1 extracellular domain 3 and 4 (D3D4) or D3 alone in the variable-constant (VH-CH1) elbow. Through mass spectrometry and binding assays, we identified a large set of RIFINs that bind to LILRB1 D3. Crystal and cryo-electron microscopy structures of a RIFIN in complex with either LILRB1 D3D4 or a D3D4-containing antibody Fab revealed a mode of RIFIN-LILRB1 D3 interaction that is similar to that of RIFIN-LAIR1. The Fab showed an unconventional triangular architecture with the inserted LILRB1 domains opening up the VH-CH1 elbow without affecting VH-VL or CH1-CL pairing. Collectively, these findings show that RIFINs bind to LILRB1 through D3 and illustrate, with a naturally selected example, the general principle of creating novel antibodies by inserting receptor domains into the VH-CH1 elbow.

PubMed: 33790470
DOI: 10.1038/s41586-021-03378-6

Experimental method

ELECTRON MICROSCOPY (3.54 Å)